4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds

ABSTRACT

Compounds of Formula 1 
     
       
         
         
             
             
         
       
         
         
           
             where X is S and the variables have the meaning defined in the specification are specific or selective to alpha 2B  and/or alpha 2C  adrenergic receptors in preference over alpha 2A  adrenergic receptors, and as such have no or only minimal cardivascular and/or sedatory activity. These compounds of Formula 1 are useful as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha 2B  adrenergic receptors. Compounds of Formula 1 where X is O also have the advantageous property that they have no or only minimal cardivascular and/or sedatory activity and are useful for treating pain and other conditions with no or only minimal cardivascular and/or sedatory activity.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation-in-part of application Ser.No. 10/153,328 filed on May 21, 2002 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 4-(substitutedcycloalkylmethyl)imidazole-2-thiones, 4-(substitutedcycloalkenylmethyl)imidazole-2-thiones and related compounds and totheir use as specific or selective agonists of alpha_(2B) and/oralpha_(2C) adrenergic receptors. More specifically the present inventionrelates to the above-noted compounds, pharmaceutical compositionscontaining these compounds as active ingredient for modulating thealpha2B and/or alpha2C adrenergic receptors, and even more specificallyfor utilizing these compounds and pharmaceutical compositions toalleviate chronic pain, allodynia, muscle spasticity, diarrhea,neuropathic pain and other diseases and conditions.

The present invention also relates to, 4-(substituted cycloalkylmethyl)imidazol-2-ones and 4-(substituted cycloalkenylmethyl)imidazol-2-onesand to pharmaceutical compositions containing these compounds alleviatechronic pain, allodynia, muscle spasticity, diarrhea, neuropathic painand other diseases and conditions.

2. Background Art

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into alpha₁, α₂, β₁, and β₂ subtypes. Functional differencesbetween α₁ and α₂ receptors have been recognized, and compounds whichexhibit selective binding between these two subtypes have beendeveloped. Thus, in published international patent application WO92/0073, the selective ability of the R(+) enantiomer of terazosin toselectively bind to adrenergic receptors of the at, subtype wasreported. The α₁/α₂ selectivity of this compound was disclosed as beingsignificant because agonist stimulation of the α₂ receptors was said toinhibit secretion of epinephrine and norepinephrine, while antagonism ofthe α₂ receptor was said to increase secretion of these hormones. Thus,the use of non-selective alpha-adrenergic blockers, such asphenoxybenzamine and phentolamine, was said to be limited by their α₂adrenergic receptor mediated induction of increased plasma catecholamineconcentration and the attendant physiological sequelae (increased heartrate and smooth muscle contraction).

For a further general background on the α-adrenergic receptors, thereader's attention is directed to Robert R. Ruffolo, Jr.,α-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology,(Progress in Basic and Clinical Pharmacology series, Karger, 1991),wherein the basis of α₁/α₂ subclassification, the molecular biology,signal transduction, agonist structure-activity relationships, receptorfunctions, and therapeutic applications for compounds exhibitingα-adrenergic receptor affinity is explored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B), and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha 2 adrenergic receptor agonist activity are knownanalgesics. However, many compounds having such activity do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoreceptors. For example, many compounds found to beeffective agents in the treatment of pain are frequently found to haveundesirable side effects, such as causing hypotension and sedation atsystemically effective doses. There is a need for new drugs that providerelief from pain without causing these undesirable side effects.Additionally, there is a need for agents which display activity againstpain, particularly chronic pain, such as chronic neuropathic andvisceral pain.

British Patent 1 499 485, published Feb. 1, 1978 describes certainthiocarbamide derivatives; some of these are said to be useful in thetreatment of conditions such as hypertension, depression or pain.

PCT Publications WO01/00586 published on Jan. 4, 2002 and WO99/28300published on Jun. 10, 1999 describe certain imidazole derivatives actingas agonists of alpha_(2B) and/or alpha_(2C) adrenergic receptors. U.S.Pat. No. 6,313,172 discloses phenylmethyl-thiourea derivatives used fortreatment of pain.

U.S. Pat. No. 4,798,843 describes (phenyl)-imidazole-2-thiones andsubstituted (phenyl)-imidazole-2-thiones.

U.S. Pat. Nos. 6,545,182 and 6,313,172 describephenylmethyl-(2hydroxy)ethylthioureas which have no significantcardiovascular or sedative effects and are useful for alleviatingchronic pain and allodynia. U.S. Pat. No. 6,534,542 describescycloalkyl, cycloalkenyl, cycloalkylmethyl andcycloalkenylmethyl(2-hydroxy)ethylthioureas and their use as specific orselective agonists of alpha_(2B) adrenergic receptors. In a differentbiological or pharmaceutical context United States Published Application20020094998, published on July 18, 2002 and claiming priority of U.S.Provisional Application No. 6/0244,850 discloses a compound withoutassigning the proper stereochemistry to it, which corresponds to twocompounds described in the present application with the properstereochemistry.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula 1

where the variable Y in the ring is optional and represents a heteroatomselected from N, O and S with the proviso that the N atom is trivalent,and the O or S atoms are divalent;

k is an integer having the values of 0 or 1;

n is an integer having the values 0, 1 or 2;

p is an integer having the values 0, 1 or 2;

X is O or S;

the dashed lines represent a bond, or absence of bond with the provisothat only one double bond is present in the ring and that two adjoiningdashed lines do not both represent a bond;

R₁, R₂, R₃, and R₄ are independently H, phenyl, said phenyl group beingoptionally substituted independently with one, two or three C₁₋₆alkyl,SO₃H, N₃, halogen, CN, NO₂, NH2, C₁₋₆alkoxy, C₁₋₆thioalkoxy,C₁₋₆alkylamino, C₁₋₆dialkylamino, C₂₋₆alkynyl, C₂₋₆alkenyl groups, 5 or6 membered heteroaryl having 1 to 3 heteroatoms selected from O, S, andN, said heteroaryl groups being optionally substituted independentlywith one, two or three C₁₋₆alkyl, SO₃H, N₃, halogen, CN, NO₂, NH₂,C₁₋₆alkoxy, C₁₋₆thioalkoxy, C₁₋₆alkylamino, C₁₋₆dialkylamino,C₂₋₆alkynyl, C₂₋₆alkenyl groups,

or said R₁, R₂, R₃, and R₄ groups being independently alkyl of 1 to 4carbons, cycloalkyl of 3 to 5 carbons, CH₂CN, CH₂SR₅, CH₂NR₆R₆, COR₅,CH₂OR₅, OR₆, SR₆. NR₆R₆, alkenyl having 1 to 4 carbons, alkynyl having 1to 4 carbons, cycloalkyl having 3 to 6 carbons, F, Cl, Br, I, CF₃, orCN, an oxygen double bonded to the ring carbon with the proviso that theadjacent dashed line within the ring represents absence of a bond;

R₅ is H, OR₇, alkyl of 1 to 4 carbons, CF₃, cycloalkyl of 3 to 6carbons, phenyl, phenyl substituted with one or two alkyl groups of 1 to4 carbons, with F, Cl, Br, I, or with CF₃, or R₅ is a 5 or 6 memberedheteroaryl having 1 to 3 heteroatoms selected from O, S, and N, and 5 or6 membered heteroaryl having 1 to 3 heteroatoms selected from O, S, andN substituted with one or two alkyl groups of 1 to 4 carbons, with F,Cl, Br, T, or with CF₃;

R₆ is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons,phenyl, phenyl substituted with one or two alkyl groups of 1 to 4carbons, with F, Cl, Br, I, or with CF₃, or R₆ is 5 or 6 memberedheteroaryl having 1 to 3 heteroatoms selected from O, S, and N, or 5 or6 membered heteroaryl having 1 to 3 heteroatoms selected from O, S, andN substituted with one or two alkyl groups of 1 to 4 carbons, with F,Cl, Br, I, or with CF₃;

R₇ is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons,phenyl, phenyl substituted with one or two alkyl groups of 1 to 4carbons, with F, Cl, Br, I, or with CF₃;

R₁ and R₂ or R₂ and R₃ or R₃ and R₄ together can form a ring togetherwith the respective carbons to which each of these is attached, theportion contributed by R₁ and R₂ or by R₂ and R₃ or by R₃ and R₄ havingthe formulas (i), (ii), (iii), (iv) or (v)

m is an integer having the values 0 to 3;

R₈ is independently H, alkyl of 1 to 6 carbons, alkenyl of 2 to 6carbons, alkynyl of 2 to 6 carbons, SO₃H, N₃, CN, NO₂, F, Cl, Br, I,CF₃, COR₉, CH₂OR₉, OR₁₀; SR₁₀, C₁₋₆alkylamino, or C₁₋₆dialkylamino,

R₉ is H, alkyl of 1 to 6 carbons, or OR₁₀, and

R₁₀ independently is H or alkyl of 1 to 6 carbons.

In a second aspect the present invention is directed to pharmaceuticalcompositions containing as the active ingredient one or more compoundsof Formula 1, the compositions being utilized as medicaments in mammals,including humans, for treatment of diseases and or alleviations ofconditions which are responsive to treatment by agonists of alpha_(2B)adrenergic receptors. The compositions containing the compounds of theinvention are primarily, but not exclusively, used for alleviation ofchronic pain and/or allodynia. The compounds where the X group is S(thiones) have the demonstrable advantageous property that they arespecific or selective to alpha_(2B) and/or alpha_(2C) adrenergicreceptors in preference over alpha_(2A) adrenergic receptors, and assuch have no or only minimal cardivascular and/or sedatory activity.Compounds where the X group is O (oxo compounds) also have theadvantageous property that they have no or only minimal cardivascularand/or sedatory activity.

DETAILED DESCRIPTION OF THE INVENTION

A general description of the compounds of the invention is provided inthe Summary section of the present application for patent with referenceto Formula 1. It will be readily apparent to those skilled in the artthat some of the compounds depicted in these formulas may exist in trans(E) and cis (Z) isomeric forms. Moreover, some of the compounds of theinvention may contain one or more asymmetric centers, such that thecompounds may exist in enantiomeric as well as in diastereomeric forms.Unless it is specifically noted otherwise, the scope of the presentinvention includes all trans (E) and cis (Z) isomers, enantiomers,diastereomers and racemic mixtures. Some of the compounds of theinvention may form salts with pharmaceutically acceptable acid or base,and such pharmaceutically acceptable salts of the compounds of Formula 1are also within the scope of the invention.

Both the imidazole-2-thione and the imidazol-2-one derivative compoundsof the present invention can undergo tautomeric transformations and canbe depicted by the tautomeric formulas shown below. All tautomers ofFormula 1 are within the scope of the invention.

Generally speaking and referring to Formula 1 in the preferred compoundsof the invention the variable p represent the integer zero (0) or one(1) and the R₁₀ groups of the moiety [C(R₁₀)₂]_(p) are hydrogen. Thus,in the preferred compounds of the invention a methylene (CH₂) groupconnects the imidazole-2-thione or imidazol-2-one nucleus with thecycloalkyl or cycloalkenyl ring shown in Formula 1, or there is no suchconnecting group.

In the preferred compounds of the invention the variable n represents aninteger having the values zero (0) or one (1) so that the cycloalkyl orcycloalkenyl ring shown in Formula 1 is preferably 5 or 6 membered.

The variables R₁, R₂, R₃, and R₄ of the preferred compounds of theinvention represent hydrogen, alkyl of 1 to 4 carbons, an oxo group, andethynyl. Alternatively in many preferred compounds of the invention twoadjacent ones of the R₁, R₂, R₃, and R₄ groups form a 5 or 6 memberedring which can be aromatic, or fully or partly saturated but morepreferably at least partly unsaturated. When the ring formed by twoadjacent ones of the R₁, R₂, R₃, and R₄ groups is heteroaromatic thenpyridyl, thienyl, furyl, pyrollyl and imidazole rings are preferred withthe thienyl, pyridyl and piperidinyl being most preferred.

The variable R₈ represents the substituent on the ring formed by twoadjacent ones of the R₁, R₂, R₃, and R₄ groups and is preferably H,alkyl of 1 to 4 carbons, OR₉, Cl, Br, F, or CH₂OH.

The presently most preferred 4-(substitutedcycloalkylmethyl)imidazole-2-thione and 4-(substitutedcycloalkenylmethyl)imidazole-2-thione compounds of the invention aredisclosed by their structural formula in Table 1 together with theiractivity in assays measuring their ability to act as agonists ofalpha_(2A), alpha_(2B) and alpha_(2C) adrenergic receptors. Thepresently most preferred 4-(substituted cycloalkylmethyl)imidazol-2-oneand 4-(substituted cycloalkenylmethyl)imidazol-2-one compounds of theinvention are disclosed by their structural formula in Table 2.

TABLE 1 (imidazole-2-thione compounds) EC₅₀ (nM) (intrinsic activity)Alpha Compound # 2A Alpha 2B Alpha 2C Compound 2 NA 81 NA

(0.81) Compound 3 NA 750 >2000

(0.49) (0.32) Compound 1 NA 5 110

(0.87) (0.43) Compound 7 NA 10 182

(0.91) (0.57) Compound 4 NA 30 602

(1.06) (0.55) Compound 32 NA 86 NA

(0.78) Compound 25 NA 106 NA

(0.97) Compound 10 NA 24 137

(0.93) (0.42) Compound 31 NA 815 NA

(0.83) Compound 29 NA 14 NA

(0.74) Compound 23 NA 18 NA and 24 (1.0)

Compound 18 NA 24 180

(0.85) (0.51) Compound 5 NA 85 677

(1.07) (1.13) Compound 6 NA 161 331

(1.0) (1.0) Compound 8 NA 578 >2000

(1.1) (0.57) Compound 9 NA 33 1022

(1.01) (1.39) Compound 19 NA 665 >2000

(1.12) (0.70) Compound 11 NA 1151 NA

(0.37) Compound 12 NA 58 939

(0.93) (0.34) Compound 13 NA 41 1113

(0.97) (0.52) Compound 36 NA 6 NA

(1.08) Compound 14 NA 1592 >2000

(0.68) (0.46) Compound 15 NA 158 2000

(0.85) (0.62) Compound 16 NA 19 349

(0.92) (0.69) Compound 17 NA 30 139

(0.94) (1.0) Compound 20 NA 260 662

(1.0) (0.75) Compound 21 NA 422 >2000

(1.11) (0.57) Compound 30 NA 17 NA

(0.65) Compound 22 NA 1618 2473

(0.88) (0.72) Compound 26 NA 523 >2000

(0.96) (0.61) Compound 27 NA 850 NA

(0.71) Compound 37 NA 25 NA

(0.61) Compound 28 NA 1008 NA

(0.48) Compound 39 NA 451 NA

(0.68) Compound 40 NA 265 NA

(0.60) Compound 38 NA 61 NA

(0.72) Compound 34 NA 29 66

(0.96) (0.47) Compound 33 NA 162 306

(0.95) (0.34) Compound 35 NA 172 107

(0.76) (0.35) Compound 23 NA 41 NA

(0.83) (−) enantiomer Compound 24 NA 92 NA

(0.79) (+) enantiomer Compound 100 NA 7.5 64

(0.95) (0.56) (+) enantiomer Compound 101 NA 24.5 629.5

(0.97) (0.61) (−) enantiomer Compound 102 NA 17 NA

(0.82) Compound 103 NA 286 —

(1.16) Compound 104 NA 28 115.5

(0.9) (0.55) Compound 105 NA 27 139

(0.95) (0.48) Compound 106 NA 755 2258

(0.98) (0.88) Compound 107 NA 720 NA

(0.6) Compound 108 NA 395 NA

(0.41) (−) enantiomer Compound 109 NA 13.7 NA

(0.93) (+) enantiomer Compound 110 NA 60 NA

(0.73) (+) enantiomer Compound 111 NA 300 NA

(0.76) Compound 141 NA 115 NA

(0.99) Compound 142 NA 110 NA

(0.65) Compound 143 NA 6 NA

(0.98) Compound 144 NA 34 423.5

(1.03) (0.52) Compound 145 NA 30 NA

(0.75) Compound 146 NA 3 13

(0.99) (0.62) Compound 147 NA 27 374

(1.12) (0.45) Compound 148 NA 28 321

(0.87) (0.38) Compound 149 NA 5 106

(1.07) (0.87) Compound 150 NA 7 92

(1.27) (0.86) Compound 151 NA 57.5 NA

(0.85) Compound 152 NA 14 561

(0.91) (0.45) Compound 153 NA 7 190

(1) (0.53) Compound 154 NA 5 NA

(1.03) Compound 155 NA 7 101

(0.96) (0.49) Compound 157 NA 34 42

(1.01) (0.63) Compound 158 NA 354 662

(0.363) (0.38) Compound 159 NA 34.5 NA

(0.93) Compound 156 NA 834 NA

(0.54) Compound 160 NA 105 NA

(0.64) Compound 161 NA 74 NA

(0.78) Compound 162 NA 1592 NA

(0.74) Compound 163 NA <2 45

(1.15) (0.74) Compound 164 NA 6.5 NA

(0.81) Compound 165 NA 22 NA

(1.02) Compound 166 NA 31.3 NA

(0.91) Compound 167 NA 87 168

(0.73) (0.59) Compound 168 NA 236 2821

(1.07) (0.46) Compound 169 NA 160 NA

(0.94) Compound 170 NA 990 NA

(0.5) Compound 171 NA 469 NA

(0.87) Compound 112 NA NA 214

(0.68) Compound 113 NA 2178 >3000

(0.47) (0.46) Compound 114 NA >3000 568

(0.56) (0.47) Compound 115 NA 498 155

(0.91) (1.01) Compound 116 NA >10000 2508

(0.63) (0.61) Compound 129 NA NA 190.5

(0.45) Compound 117 NA 190.5 916

(0.53) (0.37) (+) enantiomer Compound 118 NA NA 715.3

(0.61) (+) enantiomer Compound 119 NA 471.7 790.5

(0.83) (0.58) (+) enantiomer Compound 120 NA 1471 NA

(0.66) (−) enantiomer Compound 121 NA 269 131

(0.97) (0.72) (−) enantiomer Compound 122 NA 1599 569

(0.59) (0.68) (−) enantiomer Compound 123 NA 458.7 151.5

(0.68) (0.77) Compound 124 NA 225 205

(0.44) (0.68) Compound 125 NA 1095 2764

(0.69) (0.75) Compound 126 NA NA 240.8

(0.66) Compound 127 NA NA 994

(0.53) Compound 128 NA 219 289.5

(0.42) (0.62) Compound 130 NA NA 429.5

(0.38) Compound 131 NA 234 611

(0.53) (0.42) Compound 132 NA 103 40

(0.97) (0.52) Compound 133 NA 603 57

(0.98) (0.5) Compound 134 NA 269 NA

(0.79) Compound 135 NA 32 9

(0.9) (0.45) Compound 136 NA 22.5 34.5

(0.97) (0.82) Compound 137 NA 22 41

(0.93) (0.85) Compound 138 NA 21 92

(1.08) (0.51) Compound 139 NA 115 47

(0.89) (1.11) Compound 140 NA 51 22

(0.78) (0.95)

TABLE 2 (imidazol-2-one compounds) Compound # Compound 41

Compound 42

Compound 45

Compound 44

Compound 46

Compound 54

Compound 55

Compound 47

Compound 48

Compound 49

Compound 59

Compound 58

Compound 57

Compound 50

Compound 51

Compound 56

Compound 43

Compound 52

Compound 53

Compound 64

Compound 60

Compound 63

Compound 61

Compound 62

Reaction Scheme A illustrates a general method for obtaining the4-(substituted cycloalkylmethyl)imidazole-2-thione and 4-(substitutedcycloalkenylmethyl)imidazole-2-thione compounds of the invention. Thestarting material in this scheme is a primary alcohol of Formula 2 wherethe variables have the same definitions as in Formula 1. However thescheme is primarily applicable when one of the R₁ and R₂ substituents isnot H. Thus, the compound of Formula 2 has one C(R₁₀)₂ unit less thanthe compound of Formula 1 in the corresponding chain. However, forsimplicity of illustration the scheme discloses the preparation of thepreferred class of 4-(substituted cycloalkylmethyl)imidazole-2-thioneand 4-(substituted cycloalkenyylmethyl)imidazole-2-thione compounds ofthe invention where p is one (1) and R₁₀ is hydrogen, and the startingmaterial shown in the scheme is designated with Formula 2A. Thecompounds of Formula 2 and of Formula 2A can be obtained in accordancewith known procedures in the chemical scientific and patent literatureor by such modifications of known procedures which are readily apparentto the practicing synthetic organic chemist.

Referring still to Reaction Scheme A the primary cyclic alcohol ofFormula 2A is reacted with ethyl vinyl ether (EVE) in the presence ofmercuric ions (mercuric acetate Hg(OAc)₂) to provide the vinyl ether ofFormula 3 which is thereafter oxidized and rearranged by treatment withlithium perchlorate (LiClO₄) to provide the 4-(substitutedcycloalkyl)-acetaldehydes or 4-(substituted cycloalkenyl)-acetaldehydesof Formula 4. The aldehydes of Formula 4 are then reacted withpara-toluenesulfonyl isocyanide (tosylmethylisocyanide, TosMIC), sodiumcyanide (NaCN) and thereafter heated with ammonia in an alcohol solventto provide the 4-(substituted cycloalkylmethyl)imidazole or4-(substituted cycloalkenylmethyl) imidazole compounds of Formula 5which are preferably isolated as the fumarate salt. The 4-(substitutedcycloalkylmethyl)imidazole or 4-(substitutedcycloalkenylmethyl)imidazole compounds of Formula 5 are then reactedwith phenylchlorothionoformate (PhOC(S)Cl) to convert them to thecorresponding imidazole-2-thione compounds of Formula 6. The compoundsof Formula 6 are pharmaceutically active compounds of the invention andare within the scope of Formula 1.

Reaction Scheme B discloses another general synthetic routes to4-(substituted cycloalkylmethyl)imidazole-2-thiones and 4-(substitutedcycloalkenylmethyl) imidazole-2-thione compounds of the invention. Thissynthetic route is particularly suitable for preparation of thosecompounds of the invention where the R₁ substituent of Formula 1represents an oxo group, and where a suitably substituted cycloalkyl orcycloalkenyl group of Formula 7 is readily available commercially or inaccordance with the chemical literature. In accordance with this scheme,the keto compound of Formula 7 is heated with 4,5-imidazolecarboxaldehyde of Formula 8 in the presence of strong acid to yield(1H-imidazol-4-yl-methylene)-cycloalkyl or(1H-imidazol-4-yl-methylene)-cycloalkenyl derivatives of Formula 9.4,5-imidazole carboxaldehyde is available from Aldrich. The methylenegroup of the imidazole compound of Formula 9 is reduced by hydrogenationto provide (1H-imidazol-4-yl-methyl)-cycloalkyl or(1H-imidazol-4-yl-methyl)-cycloalkenyl derivatives of Formula 10. The(1H-imidazol-4-yl-methyl)-cycloalkyl or(1H-imidazol-4-yl-methyl)-cycloalkenyl derivatives of Formula 10 arereacted with phenylchlorothionoformate (PhOC(S)Cl), as described abovein connection with Reaction Scheme A, to obtain the thione compounds ofFormula 11. The compounds of Formula 11 are pharmaceutically activecompounds of the invention and are within the scope of Formula 1.

Reaction Scheme C discloses still another general synthetic route to thepreparation of the 4-(substituted cycloalkylmethyl)imidazole-2-thioneand 4-(substituted cycloalkenylmethyl)imidazole-2-thione compounds ofthe invention. This synthetic route is particularly suitable forpreparation of those compounds of the invention where a corresponding,suitably substituted cycloalkyl or cycloalkenyl methyl iodo (or chloroor bromo) compound of Formula 12 is available commercially or inaccordance with the chemical literature to serve as a starting material.The iodo compound is reacted with1-N-(dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole of Formula13 in the presence of n-butyl lithium to give 4-(substitutedcycloalkylmethyl or 4-(substituted cycloalkenylmethyl1-N-(dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole of Formula14. The synthesis of 1-N-(dimethylsulfamoyl)-2-tert-butyldimethylsilylimidazole is described below in the experimental section of the presentapplication for patent. The tertiary butyldimethylsilyl (TBS) group isremoved from the compound of Formula 14 by treatment withtetrabutylammonium fluoride (TBAF) to give 4-(substitutedcycloalkylmethyl or 4-(substituted cycloalkenylmethyl1-N-(dimethylsulfamoyl)-imidazole compounds of Formula 15. Treatment ofthe 4-(substituted cycloalkylmethyl or 4-(substituted cycloalkenylmethyl1-N-(dimethylsulfamoyl)-imidazole compounds of Formula 15 with strongbase, such as potassium hydroxide removes the N-(dimethylsulfamoyl)group and the resulting 4-(substituted cycloalkylmethyl or4-(substituted cycloalkenylmethyl-imidazole compounds of Formula 5 areisolated as the fumarate salt. The 4-(substituted cycloalkylmethyl or4-(substituted cycloalkenylmethyl-imidazole compounds of Formula 5 arethen reacted with phenylchlorothionoformate (PhOC(S)Cl) to convert themto the corresponding imidazole-2-thione compounds of Formula 6, as isdescribed in connection with Reaction Scheme A.

Reaction Scheme D illustrates a general method for obtaining the4-(substituted cycloalkylmethyl)imidazol-2-one and 4-(substitutedcycloalkenylmethyl) imidazole-2-one compounds of the invention. Theactual starting material in this scheme can also be the primary alcoholof Formula 2 which is shown in Reaction Scheme A, where the variableshave the same definitions as in Formula 1. Thus, the compound of Formula2 has one C(R₁₀)₂ unit less than the compound of Formula 1 in thecorresponding chain. However, for simplicity of illustration the schemediscloses the preparation of the preferred class of 4-(substitutedcycloalkylmethyl) imidazol-2-one and 4-(substitutedcycloalkenyylmethyl)imidazol-2-one compounds of the invention where p isone (1) and R₁₀ is hydrogen. Because certain initial reaction stepsfollowed in this scheme are the same as in Reaction Scheme A, thisScheme D illustrates the synthesis only from the compound of Formula 5,which is obtained as described in Scheme A. Thus the compounds ofFormula 5, preferably in the form of the fumarate salt, are reacted withphenylchloroformate (PhOC(O)Cl) in the presence of sodium bicarbonate,followed by reaction with sodium carbonate to convert them to thecorresponding imidazol-2-one compounds of Formula 16. The compounds ofFormula 16 are pharmaceutically active compounds of the invention andare within the scope of Formula 1.

Reaction Scheme E discloses another general synthetic routes to4-(substituted cycloalkylmethyl)imidazol-2-ones and 4-(substitutedcycloalkenylmethyl)imidazol-2-one compounds of the invention. Similarlyto Reaction Scheme B this synthetic route is particularly suitable forpreparation of those compounds of the invention where the R₁ substituentof Formula 1 represents an oxo group, and where a suitably substitutedcycloalkyl or cycloalkenyl group of Formula 7 as shown in ReactionScheme B is readily available commercially or in accordance with thechemical literature. In the reaction sequence disclosed in this schemethe compounds of Formula 10, obtained as shown in Reaction Scheme B, arereacted with phenylchloroformate (PhOC(O)Cl) in the presence of sodiumbicarbonate, followed by reaction with sodium carbonate to convert themto the corresponding imidazol-2-one compounds of Formula 16.

Another general presently preferred synthetic route shown in ReactionScheme F for the synthesis of the 4-(substitutedcycloalkylmethyl)imidazol-2-one and 4-(substitutedcycloalkenylmethyl)imidazol-2-one compounds of the invention isparticularly suitable for preparation of those compounds of theinvention where a corresponding, suitably substituted cycloalkyl orcycloalkenyl methyl iodo (or chloro or bromo) compound of Formula 12,shown in Reaction Scheme C, is available commercially or in accordancewith the chemical literature to serve as a starting material. Thissynthetic route follows the route shown in Reaction Scheme C to preparethe imidazole compounds of Formula 15, as shown in Scheme C. These arethereafter converted to the correspondingcycloalkylmethyl)imidazol-2-one or 4-(substitutedcycloalkenylmethyl)imidazol-2-one compounds by reactions withphenylchloroformate (PhOC(O)Cl) in the presence of sodium bicarbonate,followed by reaction with sodium carbonate to yield the correspondingimidazol-2-one compounds of Formula 16.

The reaction schemes incorporated in the experimental section of thisapplication illustrate the synthetic schemes which are employed for thesynthesis of preferred embodiments of compounds of the invention.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION

The imidazole-2-thione compounds of the invention are agonists of alpha₂adrenergic receptors, particularly they tend to be specific or selectiveagonists of alpha_(2B) and/or to a lesser extent alpha_(2C) adrenergicreceptors, in preference over alpha_(2A) adrenergic receptors. Thespecific or selective alpha_(2B) and/or to a lesser extent alpha_(2C)agonist activity of the compounds of the invention is demonstrated in anassay titled Receptor Selection and Amplification technology (RSAT)assay, which is described in the publication by Messier et. AL, 1995,Pharmacol. Toxicol. 76, pp. 308–311 (incorporated herein by reference)and is also described below. Another reference pertinent to this assayis Conklin et al. (1993) Nature 363:274–6, also incorporated herein byreference.

Receptor Selection and Amplification Technology (RSAT) Assay

The RSAT assay measures a receptor-mediated loss of contact inhibitionthat results in selective proliferation of receptor-containing cells ina mixed population of confluent cells. The increase in cell number isassessed with an appropriate transfected marker gene such asβ-galactosidase, the activity of which can be easily measured in a96-well format. Receptors that activate the G protein, Gq, elicit thisresponse. Alpha2 receptors, which normally couple to Gi, activate theRSAT response when coexpressed with a hybrid Gq protein that has a Gireceptor recognition domain, called Gq/i5.

NIH-3T3 cells are plated at a density of 2×10⁶ cells in 15 cm dishes andmaintained in Dulbecco's modified Eagle's medium supplemented with 10%calf serum. One day later, cells are cotransfected by calcium phosphateprecipitation with mammalian expression plasmids encodingp-SV-β-galactosidase (5–10 μg), receptor (1–2 μg) and G protein (1–2μg). 40 μg salmon sperm DNA may also be included in the transfectionmixture. Fresh media is added on the following day and 1–2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 μl added to 100 μl aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72–96 hr at 37° C.After washing with phosphate-buffered saline, β-galactosidase enzymeactivity is determined by adding 200 μl of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-β-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30°C. and measuring optical density at 420 nm. The absorbance is a measureof enzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The EC₅₀ and maximal effect ofeach drug at each alpha₂ receptor is determined. The efficacy orintrinsic activity is calculated as a ratio of the maximal effect of thedrug to the maximal effect of a standard full agonist for each receptorsubtype. Brimonidine, also called UK14304, the chemical structure ofwhich is shown below, is used as the standard agonist for thealpha_(2A), alpha_(2B) and alpha_(2C) receptors.

Diseases that may be treated with this invention include, but are notlimited to:MACULOPATHIES/RETINAL DEGENERATION Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Central SerousChorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, MyopicRetinal Degeneration,UVEITIS/RETINITIS/CHOROIDITIS/OTHER INFLAMMATORY DISEASES AcuteMultifocal Placoid Pigment Epitheliopathy, Behcet's Disease, BirdshotRetinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,Toxoplasmosis), Intermediate Uveitis (Pars Planitis), MultifocalChoroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), OcularSarcoidosis, Posterior Scleritis, Serpiginous Choroiditis, SubretinalFibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome, PunctateInner Choroidopathy, Acute Posterior Multifocal Placoid PigmentEpitheliopathy, Acute Retinal Pigement Epitheliitis, Acute MacularNeuroretinopathyVASUCLAR DISEASES/EXUDATIVE DISEASES Diabetic retinopathy, RetinalArterial Occlusive Disease, Central Retinal Vein Occlusion, DisseminatedIntravascular Coagulopathy, Branch Retinal Vein Occlusion, HypertensiveFundus Changes, Ocular Ischemic Syndrome, Retinal ArterialMicroaneurysms, Coat's Disease, Parafoveal Telangiectasis, Hemi-RetinalVein Occlusion, Papillophlebitis, Central Retinal Artery Occlusion,Branch Retinal Artery Occlusion, Carotid Artery Disease (CAD), FrostedBranch Angiitis, Sickle Cell Retinopathy and other Hemoglobinopathies,Angioid Streaks, Familial Exudative Vitreoretinopathy, Eales DiseaseTRAUMATIC/SURGICAL/ENVIRONMENTAL Sympathetic Ophthalmia, Uveitic RetinalDisease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,Hypoperfusion During Surgery, Radiation Retinopathy, Bone MarrowTransplant RetinopathyPROLIFERATIVE DISORDERS Proliferative Vitreal Retinopathy and EpiretinalMembranesINFECTIOUS DISORDERS Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associate with HIV Infection, Uveitic Disease Associate with HIVInfection, Viral Retinitis, Acute Retinal Necrosis, Progressive OuterRetinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, MyiasisGENETIC DISORDERS Retinitis Pigmentosa, Systemic Disorders withAccosiated Retinal Dystrophies, Congenital Stationary Night Blindness,Cone Dystrophies, Stargardt's Disease And Fundus Flavimaculatus, Best'sDisease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-LinkedRetinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy,Bietti's Crystalline Dystrophy, pseudoxanthoma elasticumRETINAL TEARS/HOLES Retinal Detachment, Macular Hole, Giant Retinal TearTUMORS Retinal Disease Associated With Tumors, Congenital Hypertrophy OfThe RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, ChoroidalOsteoma, Choroidal Metastasis, Combined Hamartoma of the Retina andRetinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumorsof the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

The results of the RSAT assay with several exemplary compounds of theinvention are disclosed in Table 1 above together with the chemicalformulas of these examplary compounds. Each number in the tablerepresents EC₅₀ in nanomolar (nM) concentration whereas the number inparenthesis in the table shows the fraction of activity of theappropriate standard which is attained by the tested compound. NA standsfor “not active” at concentrations less than 10 micromolar. As is knownEC₅₀ is the concentration at which half of a given compound's maximalactivity is observed.

Generally speaking alpha2 agonists, can alleviatesympathetically-sensitized conditions that are typically associated withperiods of stress. These include 1) the increased sensitivity to stimulisuch as intracranial pressure, light and noise characteristic ofmigraines and other headaches; 2) the increased sensitivity to colonicstimuli characteristic of Irritable Bowel Syndrome and other GIdisorders such as functional dyspepsia; 3) the sensation of itchassociated with psoriasis and other dermatological conditions; 4) muscletightness and spasticity; 5) sensitivity to normally innocuous stimulisuch as light touch and spontaneous pain characteristic of conditionslike fibromyalgia; 6) various cardiovascular disorders involvinghypertension, tachycardia, cardiac ischemia and peripheralvasoconstriction; 7) metabolic disorders including obesity and insulinresistance; 8) behavioral disorders such as drug and alcohol dependence,obsessive-compulsive disorder, Tourette's syndrome, attention deficitdisorder, anxiety and depression; 9) altered function of the immunesystem such as autoimmune diseases including lupus erythematosis and dryeye disorders; 10) chronic inflammatory disorders such as Crohn'sdisease and gastritis; 11) sweating (hyperhydrosis) and shivering; and12) sexual dysfunction.

Alpha2 agonists including alpha2B/2C agonists are also useful in thetreatment of glaucoma, elevated intraocular pressure, neurodegenerativediseases including Alzheimer's, Parkinsons, ALS, schizophrenia, ischemicnerve injury such as stroke or spinal injury, and retinal injury asoccurs in glaucoma, macular degeneration, diabetic retinopathy, retinaldystrophies, Lebers optic neuropathy, other optic neuropathies, opticneuritis often associated with multiple sclerosis, retinal veinocclusions, and following procedures such as photodynamic therapy andLASIX. Also included are chronic pain conditions such as cancer pain,post-operative pain, allodynic pain, neuropathic pain, CRPS orcausalgia, visceral pain.

A compound is considered selective agonist of alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) receptors,if the compound is at least ten (10) times more active towards eitheralpha_(2B) or towards alpha_(2C) receptors than towards alpha_(2A)receptors. It can be seen from these tables that the compounds of theinvention are specific or selective agonists of alpha_(2B) and/oralpha_(2C) adrenergic receptors within the former definition, and infact have no agonist like activity or only insignificant agonist-likeactivity on alpha_(2A) receptors.

Thus, the imidazole-2-thione compounds of the invention are useful fortreating conditions and diseases which are responsive to treatment byalpha_(2B) and/or alpha_(2C) adrenergic receptor agonists. Suchconditions and diseases include, but are not limited to, pain includingchronic pain (which may be, without limitation visceral, inflammatory,referred or neuropathic in origin) neuropathic pain, corneal pain,glaucoma, reducing elevated intraocular pressure, ischemic neuropathiesand other neurodegenerative diseases, diarrhea, and nasal congestion.Chronic pain may arise as a result of, or be attendant to, conditionsincluding without limitation: arthritis, (including rheumatoidarthritis), spondylitis, gouty arthritis, osteoarthritis, juvenilearthritis, and autoimmune diseases including without limitation, lupuserythematosus. Visceral pain may include, without limitation, paincaused by cancer or attendant to the treatment of cancer as, forexample, by chemotherapy or radiation therapy. In addition, thecompounds of this invention are useful for treating muscle spasticityincluding hyperactive micturition, diuresis, withdrawal syndromes,neurodegenerative diseases including optic neuropathy, spinal ischemiaand stroke, memory and cognition deficits, attention deficit disorder,psychoses including manic disorders, anxiety, depression, hypertension,congestive heart failure, cardiac ischemia and nasal congestion, chronicgastrointestinal inflammations, Crohn's disease, gastritis, irritablebowel disease (IBD), functional dyspepsia and ulcerative colitis.Surprisingly, although the selective alpha_(2B) or alpha_(2C) adrenergicreceptor agonist activity of the imidazole-2-one compounds cannot bedemonstrated in the RSAT assay, these compounds also are useful fortreating the same conditions.

The activity of the compounds of the invention is highly advantageousbecause the administration of these compounds to mammals does not resultin sedation or in significant cardivascular effects (such as changes inblood pressure or heart rate).

The compounds of the invention act and can be used as a highly effectiveanalgesic, particularly in chronic pain models, with minimal undesirableside effects, such as sedation and cardiovascular depression, commonlyseen with other agonists of the α₂ receptors.

The compounds of the invention may be administered at pharmaceuticallyeffective dosages. Such dosages are normally the minimum dose necessaryto achieve the desired therapeutic effect; in the treatment of chromicpain, this amount would be roughly that necessary to reduce thediscomfort caused by the pain to tolerable levels. Generally, such doseswill be in the range 1–1000 mg/day; more preferably in the range 10 to500 mg/day. However, the actual amount of the compound to beadministered in any given case will be determined by a physician takinginto account the relevant circumstances, such as the severity of thepain, the age and weight of the patient, the patient's general physicalcondition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal;particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Another aspect of the invention is drawn to therapeutic compositionscomprising the compounds of Formula 1 and pharmaceutically acceptablesalts of these compounds and a pharmaceutically acceptable excipient.Such an excipient may be a carrier or a diluent; this is usually mixedwith the active compound, or permitted to dilute or enclose the activecompound. If a diluent, the carrier may be solid, semi-solid, or liquidmaterial that acts as a excipient or vehicle for the active compound.The formulations may also include wetting agents, emulsifying agents,preserving agents, sweetening agents, and/or flavoring agents. If usedas in an ophthalmic or infusion format, the formulation will usuallycontain one or more salt to influence the osmotic pressure of theformulation.

In another aspect, the invention is directed to methods for thetreatment of pain, particularly chronic pain, through the administrationof one or more compounds of Formula 1 or pharmaceutically acceptablesalts thereof to a mammal in need thereof. As indicated above, thecompound will usually be formulated in a form consistent with thedesired mode of delivery.

It is known that chronic pain (such as pain from cancer, arthritis, andmany neuropathic injuries) and acute pain (such as that pain produced byan immediate mechanical stimulus, such as tissue section, pinch, prick,or crush) are distinct neurological phenomena mediated to a large degreeeither by different nerve fibers and neuroreceptors or by arearrangement or alteration of the function of these nerves upon chronicstimulation. Sensation of acute pain is transmitted quite quickly,primarily by afferent nerve fibers termed C fibers, which normally havea high threshold for mechanical, thermal, and chemical stimulation.While the mechanisms of chronic pain are not completely understood,acute tissue injury can give rise within minutes or hours after theinitial stimulation to secondary symptoms, including a regionalreduction in the magnitude of the stimulus necessary to elicit a painresponse. This phenomenon, which typically occurs in a region emanatingfrom (but larger than) the site of the original stimulus, is termedhyperalgesia. The secondary response can give rise to profoundlyenhanced sensitivity to mechanical or thermal stimulus.

The A afferent fibers (Aβ and Aδ fibers) can be stimulated at a lowerthreshold than C fibers, and appear to be involved in the sensation ofchronic pain. For example, under normal conditions, low thresholdstimulation of these fibers (such as a light brush or tickling) is notpainful. However, under certain conditions such as those following nerveinjury or in the herpes virus-mediated condition known as shingles theapplication of even such a light touch or the brush of clothing can bevery painful. This condition is termed allodynia and appears to bemediated at least in part by Aβ afferent nerves. C fibers may also beinvolved in the sensation of chronic pain, but if so it appears clearthat persistent firing of the neurons over time brings about some sortof change which now results in the sensation of chronic pain.

By “acute pain” is meant immediate, usually high threshold, pain broughtabout by injury such as a cut, crush, burn, or by chemical stimulationsuch as that experienced upon exposure to capsaicin, the activeingredient in chili peppers.

By “chronic pain” is meant pain other than acute pain, such as, withoutlimitation, neuropathic pain, visceral pain (including that broughtabout by Crohn's disease and irritable bowel syndrome (IBS)), andreferred pain.

The following in vivo assays can be employed to demonstrate thebiological activity of the compounds of the invention.

Sedative Activity

To test sedation, six male Sprague-Dawley rats are given up to 3 mg/kgof the test compound in a saline or DMSO vehicle by intraperitonealinjection (i.p.). Sedation is graded 30 minutes following administrationof the drug by monitoring locomotor skills as follows.

The Sprague-Dawley rats are weighed and 1 ml/kg body weight of anappropriate concentration (ie. 3 mg/ml for a final dose of 3 mg/kg) drugsolution is injected intraperitoneally. Typically the test compound isformulated in approximately 10 to 50% DMSO. The results are compared tocontrols that are injected with 1 ml/kg saline or 10 to 50% DMSO. Ratactivity is then determined 30 minutes after injection of the drugsolution. Rats are placed in a dark covered chamber and a digicomanalyzer (Omnitech Electronic) quantitates their exploratory behaviorfor a five-minute period. The machine records each time the ratinterrupts an array of 32 photoelectric beams in the X and Yorientation.

Representative Compounds 18, 23, 49 and 61 of the invention were testedin this assay intraperitoneally and up to a dose of 1 mg/kg, and werefound to have no sedative effect. The results in this test with othercompounds of the invention are also expected to show that the compoundsof the invention have no significant sedatory activity.

Effects on Cardiovascular System

To test the effect of the compounds on the cardiovascular system,typically six cynomolgus monkeys are given 500 μg/kg of the testcompound by intravenous injection (i.v.) Or 3 mg/kg by oral gavage. Theeffects of the compound on the animals' blood pressure and heart rate ismeasured at time intervals from 30 minutes to six hours followingadministration of the drug. The peak change from a baseline measurementtaken 30 minutes before drug administration is recorded using a bloodpressure cuff modified for use on monkeys.

Specifically and typically the monkeys are weighed (approximately 4 kg)and an appropriate volume (0.1 ml/kg) of a 5 mg/ml solution of the testcompound formulated in 10 to 50% DMSO is injected into the cephalic veinin the animals' arm. Cardiovascular measurements are made with a BP 100Sautomated sphygmomanometer (Nippon Colin, Japan) at 0.5, 1, 2, 4 and 6hours.

The results of this test show that the compounds of the invention haveno or only minimal detectable effect on the cardiovascular system.

Alleviation of Acute Pain

Models to measure sensitivity to acute pain have typically involved theacute application of thermal stimuli; such a stimulus causes aprogrammed escape mechanism to remove the affected area from thestimulus. The proper stimulus is thought to involve the activation ofhigh threshold thermoreceptors and C fiber dorsal root ganglion neuronsthat transmit the pain signal to the spinal cord.

The escape response may be “wired” to occur solely through spinalneurons, which receive the afferent input from the stimulated nervereceptors and cause the “escape” neuromuscular response, or may beprocessed supraspinally—that is, at the level of the brain. A commonlyused method to measure nociceptive reflexes involves quantification ofthe withdrawal or licking of the rodent paw following thermalexcitation. See Dirig, D. M. et al., J. Neurosci. Methods 76:183–191(1997) and Hargreaves, K. et al., Pain 32:77–88 (1988), herebyincorporated by reference herein.

In a variation of this latter model, male Sprague-Dawley rats are testedby being placed on a commercially available thermal stimulus deviceconstructed as described in Hargreaves et al. This device consists of abox containing a glass plate. The nociceptive stimulus is provided by afocused projection bulb that is movable, permitting the stimulus to beapplied to the heel of one or both hindpaws of the test animal. A timeris actuated with the light source, and the response latency (defined asthe time period between application of the stimulus and an abruptwithdrawal of the hindpaw) is registered by use of a photodiode motionsensor array that turns off the timer and light. Stimulus strength canbe controlled by current regulation to the light source. Heating isautomatically terminated after 20 seconds to prevent tissue damage.

Typically four test animals per group are weighed (approximately 0.3 kg)and injected intraperitonealy (i.p.) with 1 ml/kg of the test compoundformulated in approximately 10 to 50% dimethylsulfoxide (DMSO) vehicle.Animals typically receive a 0.1 mg/kg and a 1 mg/kg dose of the threecompounds. Rats are acclimated to the test chamber for about 15 minutesprior to testing. The paw withdrawal latency is measured at 30, 60 and120 minutes after drug administration. The right and left paws aretested 1 minute apart, and the response latencies for each paw areaveraged. Stimulus intensity is sufficient to provide a temperature of45–50 degrees centigrade to each rat hindpaw.

The results in this test are expected to show that the compounds of theinvention do not provide analgesic effects in this bioassay of acutepain.

Alleviation of Chronic Pain

A model in accordance with Kim and Chung 1992, Pain 150, pp 355–363(Chung model), for chronic pain (in particular peripheral neuropathy)involves the surgical ligation of the L5 (and optionally the L6) spinalnerves on one side in experimental animals. Rats recovering from thesurgery gain weight and display a level of general activity similar tothat of normal rats. However, these rats develop abnormalities of thefoot, wherein the hindpaw is moderately everted and the toes are heldtogether. More importantly, the hindpaw on the side affected by thesurgery appears to become sensitive to pain from low-thresholdmechanical stimuli, such as that producing a faint sensation of touch ina human, within about 1 week following surgery. This sensitivity tonormally non-painful touch is called “tactile allodynia” and lasts forat least two months. The response includes lifting the affected hindpawto escape from the stimulus, licking the paw and holding it in the airfor many seconds. None of these responses is normally seen in thecontrol group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra X111 down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4–S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4–L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6–0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, typically six rats per test group are administeredthe test drugs by intraperitoneal (i.p.) injection or oral gavage. Fori.p. injection, the compounds are formulated in approximately 10 to 50%DMSO and given in a volume of 1 ml/kg body weight.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6–8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441–462 (1980). The post-drug threshold iscompared to the pre-drug threshold and the percent reversal of tactilesensitivity is calculated based on a normal threshold of 15.1 grams. Theresults are expressed in percent (%) MPE, where the MPE value reflectsthe percentage reversal of pain threshold to that of a normal animal(100%). Table 3 below indicates results of this test with Compounds 1, 7and 29 of the invention, administered i.p. and in oral doses. The dosesand the observed MPE values (±SEM) are shown in the table.

TABLE 3 Activity of Compounds in Chung Model of Neuropathic Pain (% PainReversal ± SEM) Dose and Route of Administration 1 μg/kg 3 μg/kg 10μg/kg 30 μg/kg 100 μg/kg 300 μg/kg 1000 μg/kg Compd. i.p. i.p. i.p. i.p.i.p. i.p. i.p.  7 1 ± 1 23 ± 4 58 ± 8* 85 ± 6* 89 ± 7* 29 17 ± 3 61 ±11* 14 ± 2  1  9 ± 2 13 ± 2 44 ± 7* 41  3 ± 1.6 71 ± 2.8* 13 ± 1* 44 0.5± 2.9 24 ± 4.6* 46 ± 9.1* 62 ± 9.6* 82 ± 5.8* 49 2.3 ± 1.3 23 ± 3.8* 39± 7.7* 72 ± 8.2* 80 ± 6.5* 18  5 ± 2.5 35 ± 5.2* 72 ± 6.6* 71 ± 6.4* 23& 24 0.8 ± 1.9 44 ± 6.3* 69 ± 15* 65 ± 11* 80 ± 9.4* 81 ± 10* 23 0.7 ±0.8* 59 ± 5.8* 74 ± 6.1* 69 ± 10* 10 μg/kg 30 μg/kg 100 μg/kg 300 μg/kg1000 μg/kg Compd. p.o. p.o. p.o. p.o. p.o.  7 1 ± 1 56 ± 10* 58 ± 8* 61± 6*  1 29 ± 5* 18  1 ± 2 68 ± 4.4* 82 ± 5.9* 82 ± 8.1* 23 & 24 2 ± 0.681 ± 8.2* 87 ± 6.1* 96 ± 4.5* 49 43 ± 7.1* 68 ± 4.8* 74 ± 6.8* Allmeasurements 30 min following drug administration. *p value <0.001compared to pretreatment values.

The results shown in Table 3 illustrate that these compounds of theinvention significantly alleviate allodynic pain, and based on thesetest and/or on the compounds ability to activate alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) adrenergicreceptors, the compounds of the invention are expected to be useful asanalgesics to alleviate allodynia and chronic pain.

SPECIFIC EMBODIMENTS, EXPERIMENTAL EXAMPLE A Method A: Procedure for thePreparation 4-(1,2,3,4,5,6-hexahydro-pentallen-1-ylmethyl)-1,3-dihydroimidazole-2-thione (Compound 1)

A solution of 3,4,5,6-tetrahydro-2H-pentalen-1-one (Intermediate A1)(prepared in accordance with Cooke et al. J. Org Chem. 1980, 45, 1046,incorporated herein by reference) (1.5 g, 12.3 mmol) in MeOH (30 mL) andCeCl₃-7H₂O (3.6 g, 14.6 mmol) at 0° C. was treated with NaBH₄ (494 mg,14.6 mmol). The solution was allowed to warm to rt and stirring wascontinued for 30 min. Water (100 mL) and diethyl ether (150 mL) wereadded. The organic layer was dried over MgSO₄, filtered and evaporatedto dryness. The alcohol (Intermediate A2) was used in the next stepwithout further purification.

A solution of the alcohol (Intermediate A2) (0.85 g, 6.9 mmol) in ethylvinyl ether (50 mL) at rt was treated with Hg(OAc)₂ (1.75 g, 5.5 mmol)at rt for 18 h. The mixture was quenched with 5–10% KOH solution (80 mL)and the product was extracted with 50% ether:hexane (3×80 mL) and driedover MgSO₄. The organic layer was filtered and evaporated under vacuum.The crude vinyl ether (Intermediate A3) was used directly in the nextstep.

A solution of 4M LiClO₄ in ether (15 mL) was treated with the crudevinyl ether (Intermediate A3) (˜0.90 g). The mixture was allowed to stirfor 20–30 min. at rt. The reaction mixture was poured into water andextracted with ether (3×75 mL). The organic layers were combined, driedover MgSO₄ and evaporated to give the crude aldehyde (Intermediate A4).

The following preparation followed the procedure by Horne et al.Heterocycles, 1994, 39, 139, incorporated herein by reference. Asolution of the aldehyde (Intermediate A24) (0.85 g, 5.6 mmol) in EtOH(15 mL) was treated with tosylmethyl isocyanide (TosMIC available fromAldrich, 1.1 g, 5.6 mmol) and NaCN (˜15 mg, cat). This mixture wasallowed to stir at rt for 20 min. The solvent was removed in vacuo andthe residue was dissolved in ˜7M NH3 in MeOH and transferred to aresealable tube. This mixture was heated to at 100° C. for 15 h. Themixture was concentrated and purified by chromatography on SiO₂ with 5%MeOH (sat. w/NH₃):CH₂Cl₂. The imidazole was purified further as thefumarate salt (Intermediate A25).

A solution of4-(1,2,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1H-imidazole; fumaratesalt (Intermediate A25) (160 mg, 0.5 mmol) in THF (3 mL) and water (3mL) was treated with NaHCO₃ (420 mg, 5 mmol) at rt for 20 min.Phenylchloro thionoformate (available from Aldrich, 180 μL, 1.3 mmol)was added and stirring was continued for 4 h. The mixture was dilutedwith water (15 mL) and extracted with ether (3×25 mL). The organicportions were combined, dried over MgSO₄, filtered and freed of solvent.The residue was dissolved in MeOH (4 mL) and treated with NEt₃ (0.35 mL)for 18 h. The solvent was removed under vacuum and the product waswashed on a glass frit with 50% CH₂Cl₂:hexanes to give a white solid(˜50%)4-(1,2,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1,3-dihydro-imidazole-2-thione.(Compound 1)

¹H NMR (500 MHz, CDCl₃ w/TMS): δ 10.6 (s, 1H), 6.41 (s, 1H), 2.80 (brs,1H), 2.67–2.63 (m, 2H), 2.43–2.36 (m, 2H), 2.21–2.10 (m, 6H), 1.86–1.83(m, 1H).

EXAMPLE A-1 (COMPOUND 2)

Use of 3-methyl-cyclopent-2-enone (commercially available from Aldrich)in Method A produced4-(3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 2).

¹H NMR (500 MHz, CDCl₃ w/TMS): δ 11.5 (brs, 1H), 11.3 (brs, 1H), 6.43(s, 1H), 5.23 (s, 1H), 2.95 (s, 1H), 2.55–2.45 (m, 2H), 2.20 (brs, 2H),2.08–2.06 (m, 1H), 1.69 (s, 3H), 1.49–1.47 (m, 1H).

EXAMPLE A-2 (COMPOUND 3)

Use of 3-ethyl-cyclopent-2-enone (available in accordance with thepublication of Woods et. al., J. Amer. Chem. Soc. 1949, 71, 2020,incorporated herein by reference) in Method A produced4-(3-ethyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione. ¹HNMR (500 MHz, CD₃OD-d⁴): δ 6.53 (s, 1H), 5.26 (s, 1H), 2.91 (brs, 1H),2.51–2.37 (m, 2H), 2.26–2.22 (m, 2H), 2.08–2.02 (m, 3H) 1.52–1.48 (m,1H), 1.03 (t, J=8.0 Hx, 3H).

EXAMPLE A-3 (COMPOUND 4)

Use of 2,3,4,5,6,7-hexahydro-indenone (available in accordance with thepublication of Cooke et. al., J. Org. Chem., supra incorporated hereinby reference) in Method A produced4-(2,3,4,5,6,7-hexahydro-1H-inden-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 4).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.82 (s, 1H), 11.61 (s, 1H), 6.51(s, 1H), 2.71 (brs, 1H), 2.62–2.51 (m, 1H), 2.12–2.03 (m, 3H), 1.90–1.82(m, 1H), 1.56–1.36 (m, 5H).

EXAMPLE A-4 (COMPOUND 5)

Use of 2-methyl-cyclohex-2-enone (available in accordance with thepublication of Hua et. al. J. Org. Chem. 1997, 62, 6888, incorporatedherein by reference) in Method A produced4-(2-methyl-cyclohex-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 5).

¹H NMR (300 MHz, DMSO-d⁶): δ 11.89 (s, 1H), 11.65 (s, 1H), 6.55 (s, 1H),5.39 (s, 1H), 2.66–2.61 (m, 1H), 2.16–2.13 (m, 1H), 1.90 (brs, 2H), 1.65(s, 3H), 1.47–1.36 (m, 4H).

EXAMPLE A-5 (COMPOUND 6)

Use of 2-ethyl-cyclohex-2-enone (available in accordance with thepublication of Hua et. al. J. Org. Chem. supra) in the method of Aproduced4-(2-ethyl-cyclohex-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 6).

¹H NMR (300 MHz, DMSO-d⁶): δ 11.90 (s, 1H), 11.60 (s, 1H), 6.56 (s, 1H),5.40 (s, 1H), 2.65–2.50 (m, 1H), 2.30–2.10 (m, 2H), 2.00–1.92 (m, 4H),1.60–1.36 (m, 4H), 0.98 (t, J=7.5 Hz, 3H).

EXAMPLE A-6 (COMPOUND 7)

Use of indanone (commercially available from Aldrich) in Method Aproduced 4-indan-1-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 7).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.92 (brs, 1H), 11.68 (brs, 1H),7.19 (s, 1H), 7.12 (s, 3H), 6.52 (s, 1H), 3.37–3.33 (m, 1H), 2.87–2.71(m, 3H), 2.40 (dd, J=9.3, 5.4 Hz, 1H), 2.13–2.05 (m, 1H), 1.66–1.59 (m,1H).

EXAMPLE A-7 (COMPOUND 8)

Use of 2-methyl-indanone (commercially available from Aldrich) in themethod of A produced4-(2-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound8).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.97 (s, 1H), 11.67 (s, 1H),7.18–6.91 (series of m, 4H), 6.52 and 6.47 (s, 1H), 3.39–3.23 (m, 2H),3.0–2.87 (m, 2H), 2.48 (s, 3H), 2.61–2.45 (m, 2H).

EXAMPLE A-8 (COMPOUND 9)

Use of 3-methyl-indanone (commercially available from Aldrich) in MethodA produced 4-(3-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thioneas a mixture of diastereomers (Compound 9)

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.96 (s, 1H), 11.67 (s, 1H),7.19–7.08 (m, 4H), 6.58 (6.51) (s, 1H), 3.43–3.00 (series of m, 2H),2.69–2.31 (series of m, 2H), 1.99–1.94 (m, 1H), 1.71–1.67 (m, 1H), 1.20(1.18) (s, 3H).

EXAMPLE A-9 (COMPOUND 10)

Use of 3,4-dihydro-2H-naphthalen-1-one (commercially available fromAldrich) in Method A produced4-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 10).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 12.01 (s, 1H), 11.67 (s, 1H),7.24–7.04 (m, 4H), 6.54 (s, 1H), 3.20–3.01 (m, 2H), 2.69 (brs, 3H),1.80–1.40 (m, 4H).

EXAMPLE A-10 (COMPOUND 11)

Use of 5-chloro-indanone (commercially available from Aldrich) in MethodA produced 4-(5-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 11).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.95 (s, 1H), 11.68 (s, 1H),7.27–7.12 (m, 3H), 6.53 (s, 1H), 3.35–3.30 (m, 1H), 2.87–2.76 (m, 3H),2.45–2.40 (m, 1H), 2.16–2.12 (m, 1H), 1.70–1.67 (m, 1H).

EXAMPLE A-11 (COMPOUND 12)

Use of 4-methyl-indanone (commercially available from Aldrich) in MethodA produced 4-(4-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 12).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.95 (s, 1H), 11.67 (s, 1H),7.06–6.95 (m, 3H), 6.52 (s, 1H), 3.38 (brs, 1H), 2.81–2.76 (m, 2H), 2.68(m, 1H), 2.42–2.37 (m, 1H), 2.20 (s, 3H), 2.14–2.10 (m, 1H), 1.67–1.64(m, 1H).

EXAMPLE A-12 (COMPOUND 13)

Use of 5-fluoro-indanone (commercially available from Aldrich) in MethodA produced 4-(5-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 13). ¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.96 (s, 1H), 11.68(s, 1H), 7.14–6.93 (m, 3H), 6.53 (s, 1H), 3.36 (brs, 1H), 2.88–2.77(series of m, 3H), 2.44–2.39 (m, 1H), 2.16–2.14 (m, 1H), 1.71–1.69 (m,1H).

EXAMPLE A-13 (COMPOUND 14)

Use of 5-methoxy-indan-1-one (commercially available from Aldrich) inMethod A produced4-(5-methoxy-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound14).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.93 (s, 1H), 11.65 (s, 1H), 7.01(d, J=8.1 Hz, 1H), 6.78 (s, 1H) 6.71–6.68 (m, 1H), 6.51 (s, 1H), 3.70(s, 3H), 2.83–2.72 (m, 4H), 2.42–2.34 (m, 1H), 2.13–2.09 (m, 1H),1.68–1.64 (m, 1H).

EXAMPLE A-14 (COMPOUND 15)

Use of 5-bromo-indanone (commercially available from Aldrich) in MethodA produced 4-(5-bromo-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 15).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): 6 (11.95 (s, 1H), 11.68 (s, 1H), 7.41(s, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.53 (s, 1H),2.89–2.74 (m, 3H), 2.46–2.39 (m, 2H), 2.15–2.10 (m, 1H), 1.72–1.64 (m,1H).

EXAMPLE A-15 (COMPOUND 16)

Use of 6-methyl-indanone (commercially available from Aldrich) in MethodA produced 4-(6-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 16).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.93 (s, 1H), 11.65 (s, 1H),7.10–6.94 (m, 3H), 6.53 (s, 1H), 2.85–2.65 (m, 3H), 2.37 (dd, J=9.6, 5.1Hz, 1H), 2.16–2.04 (m, 1H), 1.69–1.57 (m, 1H).

EXAMPLE A-16 (COMPOUND 17)

Use of 6-methoxy-indan-1-one (commercially available from Aldrich) inMethod A produced4-(6-methoxy-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound17).

¹HNMR(300 MHz, DMSO-d⁶ w/TMS): δ 11.93 (s, 1H), 11.66 (s, 1H), 7.11–7.07(m, 1H), 6.72–6.69 (m, 2H), 6.53 (s, 1H), 3.70 (s, 3H), 3.36–3.33 (m,1H), 2.83–2.50 (m, 3H), 4.10 (dd, J=9.5, 5.4 Hz, 1H), 2.18–2.06 (m, 1H),1.69–1.64 (m, 1H).

EXAMPLE A-17 (COMPOUND 100)

Chiral HPLC of Compound 7 under the following conditions: ChiralCel OJ®column, 10% IPA:hexane, rt, uv 220 nm, 1 mL/m, produced the followingenantiomer: first eluting(+)-(R)-4-indan-1-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound100), 99% ee.

opt. rotation [α]_(D) ²⁰+33° (c 1.02 in MeOH)

¹H NMR same as Example A-6, Compound 7

EXAMPLE A-18 (COMPOUND 101)

Chiral HPLC of Compound 7 under the following conditions: ChiralCel OJ®column, 10% IPA:hexane, rt, uv 220 nm, 1 mL/m, produced the followingenantiomer: second eluting(−)-(S)-4-indan-1-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound101), 98% ee.

opt. rotation [α]_(D) ²⁰−38° (c 1.84 in MeOH) ¹H NMR same as ExampleA-6, Compound 7.

EXAMPLE A-19 (COMPOUND 102)

Use of 6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carbaldehyde (obtainedas described in Jennesken, et. al. J. Org. Chem. 1986, 51, 2162,incorporated herein by reference) in Method A produced4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-1,3-dihydro-imidazole-2-thione(Compound 102).

¹H NMR (300 MHz, DMSO-d⁶) δ 11.8 (s, 1H), 11.6 (s, 1H), 7.14–7.07 (m,4H), 6.48(s, 1H), 2.89–2.74 (m, 5H), 2.14–2.04 (m, 2H), 1.42–1.31 (m,2H).

EXAMPLE A-20 (COMPOUND 103)

Use of thiochroman-4-one (commercially available from Aldrich) used inMethod A produced4-thiochroman-4-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 103).

¹H NMR (300 MHz, CDCl₃) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.13–6.97 (m, 4H),6.60 (s, 1H), 3.16–3.12 (m, 2H), 2.87–2.84 (m, 1H), 2.59–2.56 (m, 2H),1.93–1.90 (m, 1H), 1.75 (t, J=9.0 Hz, 1H).

EXAMPLE A-21 (COMPOUND 104)

Use of 2-chloro-cyclopent-2-enone (obtained as described in Kim, et. al.Synthesis 1993, 283, incorporated herein by reference) in Method Aproduced(4-(2-chloro-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 104).

¹H NMR (300 MHz, MeOH-d⁴) δ 6.58 (s, 1H), 5.75 (s, 1H), 3.00–2.80 (m,2H), 2.40 (dd, J=9.0, 6.0 Hz, 1H), 2.32–2.21 (m, 3H), 1.75–1.65 (m, 1H).

EXAMPLE A-22 (COMPOUND 105)

Use of (2-bromo-3-methyl-cyclopent-2-enyl)-acetaldehyde (IntermediateTWELVE-2) in Method A produced4-(2-bromo-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 105).

¹H NMR (300 MHz, MeOH-d⁴) δ 6.55 (s, 1H), 3.00 (brs, 1H), 2.90 (dd,J=11.1, 3.9 Hz, 1H), 2.41–2.32 (dd, J=9.6, 5.4 Hz, 1H), 2.27–2.23 (m,2H), 2.13–2.01 (m, 1H), 1.73 (s, 3H), 1.72–1.60 (m, 1H).

EXAMPLE B Method B: Procedure for Preparation of4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 18)

A solution of 3-cyclopentene-1-carboxylic acid (Intermediate B1,available from Aldrich, 2 g, 17.8 mmol) in ether (100 mL) was treatedwith LiAlH₄ (19 mL, 1M in ether) at 0° C. for 30 min. The reactionmixture was quenched by addition of Rochelle's salt solution. Themixture was extracted with 50% Et₂O:hexanes (3×50 mL). The extracts weredried over MgSO₄, filtered and evaporated to dryness. The material(Intermediate B2) was used directly in the next step.

A solution of triphenylphosphine (10.3 g, 39 mmol) in THF (50 mL) at 0°C. was treated with diethyl azodicarboxylate (DEAD) (6 mL) and themixture was allowed to stir for about 5 min. A solution ofcyclopent-3-enyl-methanol (Intermediate B2, 1.8 g, 18.3 mmol) andacetone cynaohydrin (3.4 mL, 38 mmol) in THF (50 mL) was added viasyringe over 5 min. The mixture was allowed to stir at 0° C. for 40 min.The ice bath was removed and stirring was continued for 17 h. Themixture was quenched with water and extracted with ether. The etherlayer was dried over MgSO₄ and the mixture was carefully freed ofsolvent. The residue was purified by chromatography with 10%ether:pentane to give cyclopent-3-enyl-acetonitrile (Intermediate B3)1.16 g (60%) over two steps.

A solution of (diisobutyl aluminum hydride (DIBAL) (7 mL, 1M incyclohexane) was added to cyclopent-3-enyl-acetonitrile (IntermediateB3, 520 mg, 4.9 mmol) at −70° C. After 30 min, the mixture was quenchedwith Rochelle's salt solution. The aqueous phase was extracted withether (3×20 mL) and the combined organic layers were dried over MgSO₄,filtered and evaporated to dryness. The crude aldehyde (Intermediate B4)(0.5 g) was employed in the next step.

Formation of 4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione(Compound 18) was completed by employing the same procedure, withoutformation of the fumarate, as described in Example A, and indicatedabove in the reaction scheme.

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.8 (s, 1H) 11.6 (s, 1H) 6.56 (s, 1H)5.65 (s, 2H) 2.50–2.35 (m, 5H), 1.98–1.94 (m, 2H).

EXAMPLE C Method C: Procedure for the Preparation of4-cyclohex-2-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 19)

A solution of cyclohexenol (Intermediate Cl, available from Aldrich, 2.0g, 20.4 mmol) in triethyl orthoacetate (30 mL) and propionic acid(˜0.025 mL, cat) was heated to remove ethanol. After the ethanol wasremoved heating was continued at 145° C. for 1 h. The triethylorthoacetate was removed by simple distillation. After the residuecooled to rt the product was purified by chromatography on SiO₂ with 5%ether:hexane to give the ester (Intermediate C2) as a clear colorlessoil 1.08 g (˜31%).

A solution of the above ethyl ester (Intermediate C2, 1.0 g, 5.9 mmol)was dissolved in hexanes (50 mL) and cooled to −78° C. A solution ofDIBAL (5.8 mL 1.0 M in cyclohexane) was added dropwise. After 15 min,diethyl ether (50 mL) was added and the mixture was stirred withRochelle's salt solution (25 mL) for 10 m. The organic layer wasseparated, dried and filtered. Chromatography on SiO₂ with 7%Et₂O:hexane delivered the aldehyde (Intermediate C3) as a clearcolorless oil, 0.52 g (74%). The aldehyde (Intermediate C3) wassubjected to the Büchi protocol (Horne et al.), as described above inMethod A. The fumarate salt of the imidazole (Intermediate C4) wasobtained (25% overall). Formation of4-cyclohex-2-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 19) wascompleted by employing the same procedure as described in Example A.

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.9 (s, 1H), 11.7 (s, 1H), 6.56 (s,1H), 5.7–5.4 (m, 2H) 2.37–2.20 (m, 3H), 1.93–1.16 (series of m, 6H).

EXAMPLE D Method D: Procedure for Preparation of4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 20)

A solution of 2-cyclopentene-1-one (Intermediate D1, commerciallyavailable from Aldrich) (1.5 mL, 17.5 mmol) in CH₂Cl₂ (40 mL) at 0° C.was treated with bromine (0.86 mL, 16.6 mmol) in CH₂Cl₂ (30 mL) over 10min. (see: J. Org Chem. 1982 47, 5088 incorporated herein by reference).The mixture was allowed to stir at 0° C. for one hour. Triethylamine(3.8 mL) was added and the mixture was allowed to stir at rt for 1.5 h.The mixture was diluted with CH₂C₂, washed with 10% HCl. The combinedlayers were washed with sat. NaHCO₃, brine and dried over Na₂SO₄. Themixture was filtered and evaporated to give 2-bromo-cyclopent-2-enone(Intermediate D2, 2.85 g).

The bromoenone (Intermediate D2, ˜17.5 mmol) was dissolved in 0.4MCeCl₃.7H₂O in MeOH (66 mL) at 0° C. Sodium borohydride was addedportion-wise and stirring was continued for 10 min. after addition wascomplete. The mixture was quenched with saturated NH₄Cl and extractedwith ether. The combined organic layers were washed with sat. NH₄C₁,H₂O, brine, and dried over Na₂SO₄, filtered and evaporated to dryness.The material was purified by column chromatography 15% EtOAc:Hx to give2-bromo-cyclopent-2-enol (Intermediate D3, ˜2 g, 70% over 2 steps).

The alcohol (Intermediate D3, 16 mmol) in THF (30 mL) at 0° C. wastreated with isobutyl magnesium bromide (40 mmol). The catalyst,1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol)(NiCl₂dppp) was added in one portion and the mixture was heated toreflux for 3 h. (see: Organ et al. J. Org. Chem. 1997, 62, 1523,incorporated herein by reference). The reaction mixture was cooled to rtand quenched with sat. NH₄Cl solution. The mixture was filtered andpartitioned between brine and diethyl ether. The organic layer wasremoved and dried over Na₂SO₄, filtered and concentrated under vacuum.The oil was purified by chromatography on SiO₂ with 20% EtOAc:Hx toyield 2-isobutyl-cyclopent-2-enol (Intermediate D4). Use of2-isobutyl-cyclopent-2-enol (Intermediate D4) in Method A produced4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 20).

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.55 (s, 1H), 5.38 (s, 1H), 2.80–2.68 (m,2H), 2.26–2.18 (m, 3H), 2.03–1.73 (series of m, 4H), 1.58–1.51 (m, 1H),0.93 (d, J=6.3 Hz, 3H), 0.83 (d, J=6.3 Hz, 3H).

EXAMPLE D-1 (COMPOUND 21)

Use of vinyl magnesium bromide (commercially available from Aldrich) inMethod D produced 2-vinyl-cyclopent-2-enol. The employment of thisalcohol in Method A produced4-(2-vinyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 21).

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.55–6.43 (m, 2H), 5.74 (s, 1H), 5.27–5.06(m, 2H), 3.11 (s, 1H), 2.79 (dd, J=3.3, 11.7 Hz, 1H), 2.34–2.26 (m, 3H),2.01–1.94 (m, 1H), 1.79–1.75 (m, 1H).

EXAMPLE D-2 (COMPOUND 22)

Use of 1-propenylmagnesium bromide (commercially available from Aldrich)in Method D produced 2-propenyl-cyclopent-2-enol. Employment of thisalcohol in Method A produced the cis/trans isomers:4-(2-propenyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 22).

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.56–6.52 (m, 1H), 6.18 (6.13) (s, 1H),5.82–5.49 (m, 2H), 5.56 (s, 1H), 3.05 (m, 1H), 2.78–2.66 (m, 1H),2.33–2.15 (m, 3H), 2.04–1.87 (m, !H), 1.77 (d, J=6.3 Hz, 3H), 1.73–1.55(m, 1H).

EXAMPLE E Method E: Procedure for Preparation2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 23 and Compound 24)

1-Tetralone (commercially available from Aldrich) (Intermediate E1, 1.24g, 8.5 mmol) and 4,5-imidazole carboxaldehyde (Formula 8, (0.82 g, 8.5mmol) were added to 8.5 mL of a 40% solution of H₂SO₄. The solution washeated for 24 h at 90° C. After cooling to rt, the reaction was madebasic with excess concentrated NH₄OH. The mixture was extracted twicewith THF. The organic layers were combined and washed with brine. Theorganic layer was separated and dried over Na₂SO₄. The mixture wasfiltered and the filtrate concentrated under reduced pressure to afford˜2.2 g of a yellow solid2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E3). The crude product (Intermediate E3) was suspended inethanol (100 mL) and a palladium on carbon catalyst (10%, 0.27 g) added.The mixture was shaken in a Parr hydrogenator apparatus while under 40psi of hydrogen. After 19 h the reaction mixture was filtered throughCelite and the filtrate concentrated under reduced pressure. Columnchromatography with 5–7% MeOH:CHCl₃ afforded 0.9 g (45%) of a solidcomprising 2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E4). The synthesis of2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E5) was completed by subjecting the imidazole(Intermediate E4) to the conditions described in Method A for Example Afor the conversion to the thione (Intermediate E5).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.9 (s, 1H), 11.7 (s, 1H), 7.88 (d,J=7.5 Hz, 1H), 7.57–7.54 (m, 1H), 7.37–7.34 (m, 2H), 6.58 (s, 1H),3.08–2.97 (m, 2H), 2.86–2.85 (m, 1H), 2.43 (dd, J=9.0, 6.0 Hz, 1H), 2.08(dd, J=4.0, 4.5 Hz, 1H), 1.1 (brs, 1H).

The racemic2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E5) was separated by chiral HPLC using a ChiralPak AD4.6×220 mm (Daicel Chem. Ind. Ltd.) with isocratic flow 1.2 mL/m, 10%isopropyl alcohol in acetonitrile mobile phase at 20° C. and UV 210 nm.The first peak with 6.5 min. retention time gave Compound 23 (−) S with[α]_(D) ²⁰−66.4 (c=0.57 in 9% DMSO:MeOH). The second fraction at 14.0min. gave Compound 24 (+) R with [α]_(D) ²⁰+61.9 (c=0.63 in 10%DMSO:MeOH). The absolute stereochemistry of Compounds 23 and 24, asshown in the scheme, was assigned by derivatization followed by X-raycrystallography.

Following the procedure of Example E, fused ring compounds are reactedto yield the thione derivatives listed below.

EXAMPLE E-1 (COMPOUND 25)

5-(2-Thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-6,7-dihydro-5H-benzo[b]thiophen-4-oneis prepared by using 6,7-dihydro-5H-benzo[b]thiophen-4-one as a startingmaterial in Method E.

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.87 (s, 1H), 11.69 (s, 1H), 7.40(d, J=5.5 Hz, 1H), 7.27 (d, J=5.5 Hz, 1H), 6.57 (s, 1H), 3.13–2.98 (m,3H), 2.80–2.79 (m, 1H), 2.41 (dd, J=9.5, 6.0 Hz, 1H), 2.15–2.11 (m, 1H),1.81–1.78 (m, 1H).

EXAMPLE E-2 (COMPOUND 26)

4-Methyl-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 26 is prepared by using4-methyl-3,4-dihydro-2H-naphthalen-1-one (commercially available fromAldrich) as a starting material in Method E.

¹H NMR (300 MHz, CD₃OD-d⁴): δ diastereomers: 7.99–7.90 (m, 1H),7.60–7.48 (m, 2H), 7.36–7.31 (t, J=9 Hz, 1H), 6.62 (6.60) (s, 1H),3.19–3.12 (m, 2H), 2.90–2.82 (m, 1H), 2.63 (dd, J=7.5, 9.0 Hz, 1H),2.17–1.98 (m, 1H), 1.57–1.44 (m, 1H), 1.40 (t, J=7.0 Hz, 3H).

EXAMPLE E-3 (COMPOUND 27)

2-(2-Thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-indan-1-one (Compound27) is prepared by using indanone (commercially available from Aldrich)as starting material in Method E.

¹H NMR (300 MHz, 300 MHz, CD₃OD-d⁴): δ 7.72–7.38 (m, 4H), 6.61 (s, 1H),3.38–3.33 (m, 1H), 3.08–2.99 (m, 2H), 2.87 (dd, J=13.2, 4.1 Hz, 1H),2.67–2.60 (m, 1H).

EXAMPLE E-4 (Compound 28)

6-Hydroxy-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-oneis prepared by substituting 6-hydroxy-3,4-dihydro-2H-naphthalen 1-one(commercially available from Aldrich) in Method E.

¹H NMR (300 MHz, CD₃OD-d⁴): δ 7.85 (d, J=8.8 Hz, 1H), 6.81 (s, 1H), 6.70(dd, J=6.1, 2.4 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 3.22 (dd, J=3.8, 10.6Hz, 1H), 2.92–2.88 (m, 2H), 2.78–2.62 (m, 2H), 2.14–2.09 (m, 1H),1.78–1.70 (m, 1H).

EXAMPLE E-5 (COMPOUND 106)

Use of 7,8-dihydro-6H-quinolin-5-one (obtained as described in Huang, etal, Synthetic Communications, 1998, 28, 1197, incorporated herein byreference) in Method E produced6-(1H-imidazol-4-ylmethyl)-2,3,4,6,7,8-hexahydro-1H-quinolin-5-one as aside product of the reduction step. This reduced material was used inMethod E to produce6-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-2,3,4,6,7,8-hexahydro-1H-quinolin-5-one(Compound 106).

¹H NMR (300 MHz, MeOH-d⁴) δ 6.58 (s, 1H), 3.25–3.21 (m, 2H), 2.95 (dd,J=6.6, 2.2 Hz, 1H), 2.57 (dd, J=5.4, 3.9 Hz, 1H), 2.47–2.30 (m, 5H),1.96–1.92 (m, 1H), 1.80–1.76 (m, 2H), 1.63–1.56 (m, 1H).

EXAMPLE E-6 (COMPOUND 107)

Use of 7,8-dihydro-6H-quinolin-5-one (obtained as described in Huang,et. al. Synthetic Communications, 1998, 28, 1197, incorporated herein byreference) in Method E produced6-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one(Compound 107).

¹H NMR (300 MHz, MeOH-d⁴) δ 8.46 (dd, J=4.8, 1.8 Hz, 1H), 8.33 (dd,J=7.8, 1.5 Hz, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 6.63 (s, 1H),3.22–3.12 (m, 3H), 2.95–2.85 (m, 1H), 2.71–2.63 (dd, J=4.8, 3.3 Hz, 1H),2.30–2.21 (m, 1H), 1.94–1.81 (m, 1H).

EXAMPLE F (COMPOUND 29) Method F: Procedure for Preparation of4-(4,5,6,7-Tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3dihydro-imidazole-2-thione (Compound 29)

5-(1H-Imidazol-4-ylmethyl)-6,7-dihydro-5H-benzo[b]thiophen-4-one(Intermediate F1, an intermediate already prepared by Method E in thesynthesis of Example E-1, Compound 25, 0.44 g, 1.90 mmol) was added tomethanol (20 mL). Sodium borohydride (74 mg, 1.95 mmol) was added to thesolution. After stirring for 2.5 h at rt the reaction mixture wasquenched with water. The mixture was extracted twice with ethyl acetate.The organic layers were combined and washed with brine. The organiclayer was separated and dried over Na₂SO₄. The mixture was filtered andthe filtrate concentrated under reduced pressure to afford 0.4 g of awhite solid5-(1H-imidazol-4-ylmethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol(Intermediate F2). The crude product (Intermediate F2) was dissolved inCH₂Cl₂ (25 mL). Triethylsilane (2.5 mL, 15.6 mmol) and triflouroaceticacid (4.8 mL, 62 mmol) were added and the mixture was stirred at rt for22 h. The solution was made basic with 2N NaOH and the organic layerseparated and washed with brine. The solution was dried over Na₂SO₄. Themixture was filtered and the filtrate concentrated under reducedpressure. Column chromatography with 7% methanol in chloroform afforded0.39 g (80%) of Intermediate F3. The product was dissolved in methanoland an excess of hydrogen chloride (HCl) in ether was added. Thesolution was concentrated under reduced pressure to yield 0.3 g of asolid. Column chromatography with 7% methanol in chloroform afforded0.21 g (˜45%) of the hydrochloride salt of4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazole-2-thione(Intermediate F3), as white crystals after recrystallization from amixture of acetone and methanol. The synthesis of4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 29) was completed by subjecting the hydrochloride salt of theimidazole (Intermediate F3) to the conditions described in Method A forthe synthesis of Compound 1 (Example A)4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 29):

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.9 (s, 1H), 11.7 (s, 1H), 7.22 (d,J=5 Hz, 1H), 6.75 (d, J=5 Hz, 1H), 6.60 (s, 1H), 2.80–2.59 (series of m,4H), 2.42–1.87 (series of m, 4H), 1.43–1.35 (m, 1H).

EXAMPLE F-1 (COMPOUND 30)

4-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 30) is prepared by using2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one as astarting material (see: method E above in Method F.

¹H NMR (300 MHz, CD₃OD-d⁴): δ 7.03–7.01 (m, 4H), 6.60 (s, 1H), 2.82–2.76(m, 3H), 2.52 (d, J=6.7 Hz, 11H), 2.45 (dd, J=10.3, 6.4 Hz, 11H),2.01–1.92 (m, 3H), 1.43–1.39 (m, 1H).

EXAMPLE F-2 (COMPOUND 108)

4-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-1H-imidazole (prepared bythe process in Method F) was separated by chiral HPLC under thefollowing conditions: ChiralPakAD® column, with 10% EtOH:hexane. Thefirst fraction eluted was4-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-1H-imidazole and it wasconverted to(−)-(S)-4-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 108) by the applicable process steps described in Method A.

opt. rotation [α]_(D) ²⁰−85° (c 0.75 in MeOH:DMSO 1:1) ¹H NMR same asCompound 30.

EXAMPLE F-3 (COMPOUND 109)

(+)-(R)-4-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazole-2-thionewas isolated as the second fraction in accordance with the methodreported for Example F-2 (Compound 109).

opt. rotation [α]_(D) ²⁰+780 (c 1.25 in DMSO) ¹H NMR same as Compound30.

EXAMPLES G AND G-1 (COMPOUND 31 AND COMPOUND 32) Procedure forPreparation of2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-oneand4-(1,2,3,4,5,6,7,8-octahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 31 and Compound 32)

1-Decalone (Intermediate G1, commercially available from Aldrich) (10.0g, 66 mmol) and 4(5)-imidazole carboxaldehyde (Formula 8, 6.3 g, 66mmol) were added to EtOH (100 mL). NaOH (5.2 g, 130 mmol) in H₂O (20 mL)was added and the mixture was heated at reflux for 5 days. The mixturewas cooled to rt and acidified with aqueous HCl. The solution wasextracted with THF/ethyl acetate and the organic layers were combinedand washed with brine. The organic phase was dried over MgSO₄, filteredand freed of solvent. The crude product was heated at reflux in 40%H₂SO₄ for 24 h. The reaction was cooled to rt and made basic withsaturated K₂CO₃. The solution was extracted with THF/ethyl acetate andthe organic layers were combined and washed with brine. The organicphase was dried over MgSO₄ and the solvent removed under reducedpressure. Purification by flash chromatography (15:1 CH₃Cl/MeOH)afforded Intermediate G2 (4.9 g, 32% yield).

The synthesis of compound2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one(Compound 31) was completed by subjecting the imidazole (IntermediateG2) to the applicable process steps described in Method A in connectionwith Example A. Compound 31:

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.8 (s, 1H), 11.7 (s, 1H), 6.52 (s,1H), 2.89 (dd, J=4, 4.5 Hz, 1H), 2.29–1.47 (series of m, 14H).

The free base of the hydrochloride salt of Intermediate G2 (3.0 g, 11mmol) was generated with NaOH and then added to diethylene glycol (100mL). To the solution was added hydrazine hydrate (3.2 mL, 100 mmol) andthe mixture was stirred overnight at rt. NaOH (3.1 g, 77 mmol) was addedand the solution heated at reflux for 5 days. The solution was cooled tort and diluted with water. The aqueous layer was extracted withTHF/ethyl acetate. The organic layers were combined, washed with brine,dried MgSO₄ and the solvent removed under reduced pressure. Purificationby flash chromatography (8:1 CH₃Cl:MeOH) afforded Intermediate G3 (0.64g, 27% yield).

4-(2,3,4,4a,5,6,7,8-Octahydro-naphthalen-2-ylmethyl)-1H-imidazole(Intermediate G3) (1.0 g, 4.6 mmol) was added to 10 mL of concentratedHCl. The solution was stirred at rt for 30 m and neutralized with K₂CO₃.The solution was extracted with THF/ethyl acetate. The organic layerswere combined and washed with brine, and dried over MgSO₄. The solventwas removed under reduced pressure. Purification by flash chromatography(15:1 CH₃Cl/MeOH) gave Intermediate G4.

The synthesis of compound4-(1,2,3,4,5,6,7,8-octahydro-naphthalenylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 32) was completed by subjecting the imidazole Intermediate G4to the applicable process steps described in Method A in connection withExample A. Compound 32:

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.8 (s, 1H), 11.6 (s, 1H), 6.54 (s,1H), 2.28 (d, J=6.5 Hz, 2H), 1.88–1.45 (m, 14H), 1.11 (brs, 1H).

EXAMPLE G2 (COMPOUND 110)

Intermediate G4 was separated by chiral HPLC: ChiralPakAD® column, with10% EtOH:hexane. Use of(R)-4-(1,2,3,4,5,6,7,8-octahydro-naphthalen-2-ylmethyl)-1H-imidazole) inthe applicable process steps described in Method A produced(1,2,3,4,5,6,7,8-octahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 110)

¹H NMR same as Compound 32.

EXAMPLE H (COMPOUND 33) Method H: Procedure for Preparation of8-Hydroxymethyl-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 33)

1,2,3,4-Tetrahydro-naphthalen-1-ol (Intermediate H1 commerciallyavailable from Aldrich, 13 mL, 93 mmol) was dissolved in dry hexane (300mL) and heated to 70° C. A solution of nBuLi (75 mL, 2.5M in hexane) andN,N,N′,N′-tetramethylethylenediamine(TMEDA) 28 mL) in dry hexane (30 mL)was added dropwise via an addition funnel to the solution. The additionwas completed and heating was continued for 2 h. The mixture was cooledto 0° C. and CO₂ gas was bubbled through the mixture for 8–12 h. Thesolution was stored at rt for 24 h before dilution with H₂O andacidification with 3N HCl and conc. HCl until pH ˜2. The aqueous layerwas extracted with ethyl acetate. The organic layer was extracted withsat NaHCO₃ (3×) and the combined basic aqueous extracts were cooled to0° C. and acidified with 3N HCl to HCl until a pale yellow solidprecipitated. The resulting carboxylic acid (Intermediate H2) (28%) wascollected by filtration and dried under vacuum.

Intermediate H2, was used in the next step without further purification.It was dissolved in THF (70 mL) and added dropwise to a solution ofLiAlH₄ (28 mL, 1M in THF). The reaction was stirred at rt for 1 h andheated to reflux (90° C.) for 2 h. The mixture was cooled to rt,quenched with Rochelle's salt solution and stirred for 1 h. The aqueouslayer was separated and extracted with ethyl acetate. The organic layerswere combined, dried over MgSO₄, filtered and freed of solvent to give8-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1-ol (Intermediate H3)(57%) as a white solid that was sufficiently pure for the subsequentprocess steps.

The diol (Intermediate H3) (2.42 g, 13.5 mmol) was dissolved in CH₂Cl₂(75 mL) and reacted with dihydropyran (1.3 mL, 13.8 mmol) and pyridiniumpara-toluene sulfonate (PPTS) (350 mg, 1.36 mmol) at rt for 18 h. Themixture was concentrated onto SiO₂ and purified by chromatography with10% EtOAc:Hx. The tetrahydropyranyl (THP) protected alcohol (2.02 g,7.70 mmol) was dissolved in CH₂Cl₂ (10 mL) and added to a mixture ofpyridinium chlorochromate (PCC) (4.9 g, 22.2 mmol), sodium acetate (310mg, 3.56 mmol) and celite (˜10 g) in CH₂Cl₂ (100 mL). The mixture wasreacted at rt for 18 h and filtered through celite. The residue waspurified by chromatography on SiO₂ with 20 to 30% EtOAc:Hx to yield8-(tetrahydro-pyran-2-yloxymethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate H4) (˜55%).

The THP-protected ketone (Intermediate H4) was dissolved in EtOH (15 mL)and reacted with imidazole carboxaldehyde (Formula 8, 0.50 g, 5.1 mmol)and 2N NaOH (2 mL) at reflux for 36 h. The mixture was cooled to rt andsubjected to a standard aqueous work-up. The crude residue washydrogenated in a mixture of EtOH (150 mL) and Pd (160 mg, 10% on C)under 40 psi of H₂. After 18 h at rt the THP protected compound wasisolated (12%). The THP group was removed in a mixture of acetic acid (4mL), THF (2 mL) and H₂O (1 mL) at 80° C. over 4 h. The mixture was madeslightly basic and extracted with EtOAc. The organic layer was driedover MgSO₄, filtered and concentrated. The synthesis of the8-hydroxymethyl-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 33) was completed by subjecting the imidazole compoundIntermediate H4 to the applicable process steps described in Method A inconnection with Example A. Compound 33:

¹H NMR (300 MHz, CD₃OD-d⁴) δ 7.59–7.47 (m, 2H), 7.23 (d, J=7.5 Hz, 1H),6.61 (s, 1H), 4.98–4.88 (m, 2H), 3.13–3.04 (m, 2H), 2.87–2.79 (m, 1H),2.64 (dd, J=4.5, 7.2 Hz, 1H), 2.20–2.11 (m, 1H), 1.85–1.71 (m, 1H).

EXAMPLE I (COMPOUND 34) Procedure for the Preparation8-methyl-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 34)

8-(Tetrahydro-pyran-2-yloxymethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate H4) (obtained in Method H, 550 mg, 2.11 mmol) washydrogenated with H₂ (balloon) and 10% Pd/C (190 mg) at rt for 18 h. Themixture was filtered through celite and the crude product was isolatedby evaporation of the solvent under reduced pressure.8-Methyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 12) was subjectedto the applicable process steps of Method E to produce (Compound 34).

¹H NMR (300 MHz, CD₃OD-d⁴) δ 7.32 (t, J=7.7 Hz, 1H), 7.13–7.08 (m, 2H),6.60 (s, 1H), 3.05–3.00 (m, 3H), 3.82–2.58 (m, 2H), 2.57 (s, 3H),2.16–2.09 (m, 1H), 1.82–1.73 (m, 1H).

EXAMPLE J Procedure for Preparation of8-Fluoro-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 35)

5,6,7,8-Tetrahydro-naphthalen-1-ylamine (Intermediate J1, commerciallyavailable from Aldrich) (5 mL, 35.3 mmol) was dissolved in CH₂Cl₂ (40mL) and treated with NEt₃ (10 mL) and acetyl chloride (3.8 mL, 53 mmol)at rt for 1 h. The mixture was diluted in CHCl₃ and acidified with satNH₄Cl. The aqueous layer was extracted with CHCl₃. The organic fractionswere combined, dried and evaporated and the amide was used withoutfurther purification. The resulting amide (35.3 mmol) in acetone (450mL) and aqueous MgSO₄ (5 g in 28 mL) at 0° C. was treated with KMnO₄(16.8 g, 105 mmol). The mixture was allowed to stir at 0° C. for 2 h.The mixture was diluted with H₂O and extracted several times with CHCl₃.The pooled fractions were washed with brine and dried over MgSO₄,filtered and evaporated to dryness. The residue was purified bychromatography on SiO₂ to giveN-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-acetamide (Intermediate J2)as a yellow oil. (57%, in two 2 steps)

The amide (Intermediate J2, 4.12 g, 20.3 mmol) was heated at 90° C. in6N HCl (140 mL) for 3 h. The mixture was cooled to rt and Na₂CO₃ wasadded in small portions followed by addition of 2N NaOH until themixture was at pH 8. The aqueous layer was extracted with EtOAc and theorganic fractions were combined, washed with brine, dried, filtered andconcentrated to give 8-amino-3,4-dihydro-2H-naphthalen-1-one(Intermediate J3) as a dark red solid 1.82 g (56%).

The amine (Intermediate J3, 1.83 g, 11.3 mmol) in CH₂Cl₂ (17 mL) wasadded to BF₃.OEt₂ (2.80 mL, 22.1 mmol) at −15° C. More CH₂Cl₂ (20 mL)was added to the precipitate. Next, t-butyl nitrite (1.8 mL, 12.9 mmol)in CH₂Cl₂ (20 mL) was added at −15° C. and stirred for 10 min. and at 0°C. for 20 m. The mixture was diluted with pentane (40 mL), filtered andthe solids were collected, washed with ether, and dried under vacuum.The solids were placed in a flask and heated to 115° C. for 10–15 min.followed by addition of 2N NaOH and CHCl₃. The suspension was filteredand the aqueous phase was extracted with CHCl₃. The organic layers werecombined, dried over MgSO₄, filtered and purified by chromatography onSiO₂ with 15% EtOAc:Hx. The product,8-fluoro-3,4-dihydro-2H-naphthalen-1-one (Intermediate J4) was isolated;750 mg (40%).

8-Fluoro-3,4-dihydro-2H-naphthalen-1-one (Intermediate J4) was subjectedto the applicable process steps of method E to produce (Compound 35).

¹H NMR (300 MHz, CD₃OD-d⁴) δ 7.53–7.46 (m, 1H), 7.12 (d, J=7.4 Hz, 1H),7.02 (dd, J=8.2, 3.5 Hz, 1H), 6.61 (s, 1H), 3.12–3.04 (m, 3H), 2.88–2.78(m, 1H), 2.62 (dd, J=8.2, 7.1 Hz, 1H), 2.20–2.11 (m, 1H), 1.86–1.75 (m,1H).

EXAMPLE J-1 (COMPOUND 111)

Use of 6-amino-3,4-dihydro-2H-naphthalen-1-one (commercially availablefrom Aldrich) in the applicable process steps in Method J produced6-fluoro-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 111).

¹H NMR (300 MHz, MeOH-d⁴) δ 8.05–8.00 (m, 1H), 7.08–7.00 (m, 2H), 6.61(s, 1H), 3.16–3.10 (m, 1H), 3.07–2.98 (m, 2H), 2.86–2.76 (m, 1H), 2.64(dd, J=8.1, 7.8 Hz, 1H), 2.20–2.13 (m, 1H), 1.87–1.73 (m, 1H).

EXAMPLE K (COMPOUND 36) Procedure for the Preparation of4-(3-ethyl-4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 36)

8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate K1, 1.02g, 3.70 mmol) (prepared in accordance with the publication Ciufolini et.al. J. Amer. Chem. Soc. 1991, 113, 8016, incorporated herein byreference) was dissolved in acetone (100 mL): H₂O (5 mL) and reactedwith TsOH (140 mg, 0.74 mmol) at 45° C. for 5 h. After a standardaqueous work-up the material was purified by chromatography on SiO₂ togive 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless oil (97%).

A solution of LDA (33 ml, 1.5 M in Et₂O) in THF (50 mL) at −78° C. wastreated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). Themixture was warmed to 0° C. over 30 min. before re-cooling to −78° C.and adding HMPA (7 mL). Methyl cyanoformate (CNCO₂Me, 4.1 mL, 85 mmol)was added and the mixture was stirred for 15 m before aqueous quench andwork-up. The product was purified by chromatography on SiO₂ with 10%EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-)cyclohexanecarboxylic acid methylester was isolated, 5.8 g (49%).

A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acidmethyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution(16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol)was added via syringe and the mixture was stored at rt for 48 h. Anotherportion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixturewas allowed to react until the starting material was not present (byTLC). The solution was quenched with an aqueous work-up and theresultant residue was purified by chromatography to yield5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methylester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2)was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. Themixture was cooled to 0° C. and acidified with HCl. The solution waswarmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixturewas neutralized to pH 7 with NaOH and the organic material was recoveredby extraction with chloroform. The resulting4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) wasisolated by standard work-up and used without further purification(88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL)and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rtfor 1 h. The organic material was isolated from an aqueous, acidicwork-up and purified by chromatography to give4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%).4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol)and TsOH—H₂O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100mL) for 18 h in the presence of MgSO₄ (˜250 mg). After an aqueouswork-up and chromatographic purification, the product[2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene(Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).

The benzyl protected alcohol (Intermediate K4, 5 mmol) in THF (20 mL)was cooled to −70° C. and NH3 was condensed in the same flask (˜20 mL).Na chunks were added and the mixture was allowed to stir at −70° C. for15 min. The mixture was warmed to −30° C. for 20 min. The mixture wasquenched with NH₄Cl and isolated by extraction. The residue was purifiedby chromatography on SiO₂ with 25% EtOAc:Hx (99%).

The deprotected alcohol was oxidized by the standard “Swern” procedure(Mancuso, Synthesis 1981 p165, incorporated herein by reference) asfollows: The alcohol (5 mmol) was added to a solution of oxalyl chloride(3.5 mL, 7.0 mmol) in CH₂Cl₂ (30 mL) with DMSO (0.64 mL, 9.0 mmol) at−78° C. After 40 min., NEt₃ (2.50 mL) was added and the mixture waswarmed to rt. After standard aqueous work-up and purification,(3-ethyl-4-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate K5) wasisolated (90%).

The (Intermediate K5) was converted to4-(3-ethyl-4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 36) by applying the applicable process steps of Method A.

¹H NMR (300 MHz, CD₃OD) δ 6.54 (s, 1H), 2.40 (d, J=7.0 Hz, 2H),2.02–1.95 (m, 4H), 1.83–1.67 (m, 4H), 1.59 (s, 3H), 1.25–1.15 (m, 1H).

EXAMPLE L Procedure for the Synthesis of1-dimethylsulfamoyl-2-t-butyldimethylsilyl Imidazole (Formula 13)

Imidazole (Intermediate L1, available from Aldrich, 20.0 g, 0.29 mol),triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride(31.6 mL, 0.29 mol) were added to benzene (320 mL). The reaction wasstirred for 48 h at rt and then filtered. The filtrate was collected andconcentrated under reduced pressure. Vacuum distillation of the crudeproduc (˜0.5 mmHg, 115–118° C.) afforded dimethylsulfamoyl)imidazole(Intermediate L2) 38.7 g (76%) as a clear and colorless oil. Uponcooling the product solidifies to give white crystals.1-(Dimethylsulfamoyl)imidazole (Intermediate L2) (18.8 g, 0.11 mol) wasadded to THF (430 mL). The solution was cooled to −78° C. A solution ofn-BuLi (70.9 mL, 1.6 M in hexane) was added dropwise to the reactionmixture. Upon completion, the solution was stirred for 1 h at −78° C.t-Butyldimethylsilylchloride (TBSCI) (17.8 g, 0.12 mol) in THF (50 mL)was added via cannula to the mixture. After the addition was completedthe reaction mixture was warmed slowly to rt and stirred for 24 h. Themixture was diluted with water and the organic layer separated. Theorganic phase was washed with brine and then dried over Na₂SO₄. Themixture was filtered and the filtrate concentrated under reducedpressure. Column chromatography on SiO₂ with 20% ethyl acetate/hexaneafforded 1-dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (Formula13) as a light yellow solid. Recrystallization from pentane gave 30 g(94%) of white crystals.

EXAMPLE M (COMPOUND 37) Procedure for the Preparation of4-(3,4-dimethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 37)

2,3-Dimethyl-1,3-butadiene (available from Aldrich, 10.2 g, 123.7 mmol),ethyl acrylate (11.1 g, 110.5 mmol) and hydroquinone (0.12 g, 1.11 mmol)were heated with stirring at 165° C. in a sealed tube for 16 h and thenat 205° C. for an additional 4 h. Kugelrohr distillation of theresulting residue at 150° C. and 0.5 torr gave 14.1 g (70%) ofcyclohexene ester (Intermediate M1) as an oil. To a solution of theester (Intermediate M1, 13.6 g, 72.3 mmol) in THF (200 mL) at −78° C.was added a LiAlH₄ (54.3 mL, 1 M in diethyl ether). This mixture wasstirred for 1 h at 20° C. and then quenched at 0° C. by careful,addition of H₂O (2 mL), NaOH (2 mL of a 15% aqueous solution), and anadditional portion of H₂O (6 mL). The solids were filtered off and thefiltrate was concentrated under reduced pressure. Kugelrohr distillationof the resulting residue at 150–180° C. and 0.5 torr gave 10.0 g (98%)of the alcohol (Intermediate M2) as a colorless volatile oil in the 0°C. bulb. To a solution of triphenyl phosphine (27.1 g, 103.5 mmol), andimidazole (7.04 g, 103.5 mmol) in anhydrous benzene (450 ml) under argonwas added 12 (22.8 g, 89.6 mmol) in benzene (170 ml) over a period of 10minutes with rapid mechanical stirring. After an additional 10 min. thealcohol (Intermediate M2, 9.23 g, 65.9 mmol) in benzene (100 ml) wasadded to this rapidly stirring mixture over a period of 5 min. After 2 hthe reaction was diluted with hexanes (800 ml) and the solids werefiltered off. The organics were washed with 3 portions of H₂O (800 ml),dried (MgSO₄), filtered and concentrated under reduced pressure. Theresidual solids were filtered off and the resulting oil was purified bykugelrohr distillation at 200° C. and 0.5 torr to give 12.0 g (73%) ofthe iodide (Intermediate M3) as a pale oil in the 0° C. bulb. To asolution of 1-N-(dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole(Formula 13, 4.34 g, 15.0 mmol) in anhydrous THF (50 ml) at −78° C.under argon was added n-BuLi (5.76 ml, 2.5 M in hexanes). This mixturewas stirred for 10 min. at −10° C. and then cooled to −20° C. beforeadding the iodide (Intermediate M3, 3.00 g, 12.00 mmol) in THF (25 ml)dropwise via cannula. The resulting solution was stirred for 16 h at 20°C., then quenched with saturated aqueous NaHCO₃ and concentrated underreduced pressure. The residues were taken up in diethyl ether and washedconsecutively with H₂O and brine, dried (MgSO₄) and concentrated.Subsequent purification by chromatography on SiO₂ with 5–10%EtOAc:hexanes gave 0.89 g (15%) of the imidazole derivative(Intermediate M4) as a pale oil. To a solution of Intermediate M4 (0.89g, 2.17 mmol) in anhydrous THF (25 ml) under argon was addedtetrabutylammonium fluoride (2.38 ml, 1 M in THF) and the resultantsolution was stirred for 1 h at 20° C. The mixture was concentratedunder reduced pressure and the residues were diluted with diethyl etherand washed consecutively with saturated aqueous NaHCO₃ and brine, dried(MgSO₄) and concentrated. The residues were purified by chromatographyon SiO₂ with 50% EtOAc:Hx to give 0.56 g (87%) of the imidazolederivative Intermediate M5 as a pale oil. To a solution of IntermediateM5 (0.53 g, 1.77 mmol) in MeOH (5 ml) was added aqueous KOH (15 ml of a5M solution) and the mixture was heated at reflux for 32 h. The mixturewas concentrated under reduced pressure, diluted with H₂O (5 ml) andextracted exhaustively with CHCl₃. The combined organic fractions werewashed consecutively with H₂O and brine, dried (MgSO₄) and concentratedunder reduced pressure. The product was recrystallized by stirring inMeOH with an equimolar amount of fumaric acid until all solids haddisappeared followed by the addition of a small amount of diethyl ether.4-(3,4-Dimethyl-cyclohex-3-enylmethyl)-1H-imidazole-fumarate 0.27 g(57%) was recovered as pale yellow crystals.4-(3,4-Dimethyl-cyclohex-3-enylmethyl)-1H-imidazole-fumarate wasconverted to4-(3,4-dimethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 37) by using the applicable process steps of Method A.

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.54 (s, 1H), 2.40 (d, J=6 Hz, 2H),1.95–1.66 (m, 5H), 1.59 (s, 6H), 1.29–1.18 (m, 2H)1.

EXAMPLE N (COMPOUND 38) Method N: Procedure for the Preparation of4-(4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 38)

To a slurry of NaH (60% in oil) (6.92 g, 288 mmol) in anhydrous THF(1500 mL) at 0° C. under argon with vigorous mechanical stirring addedthe trimethyl phosphonoacetate (available from Aldrich, 52.5 g, 288mmol) dropwise. Stirred this mixture an additional 30 min. before addingthe 1,4-cyclohexanedione mono-ethylene ketal (available from Aldrich, 41g, 260 mmol) in THF (170 mL) dropwise. The mixture was stirred anadditional 18 h at 20° C. and then concentrated under reduced pressure.This residue was taken up in diethyl ether (1 L) and washed with H₂O andbrine, dried (MgSO₄), filtered and concentrated to give 60 g (98%) ofthe unsaturated ester (Intermediate N1) which was used in the nextreaction step without further purification. To a solution of theunsaturated ester (Intermediate N1) in EtOAc (500 mL) was added Pd (10wt. % on activated carbon) (2.13 g). This slurry was saturated with H₂by repeated evacuations and H₂ backfills and then stirred for 16 h undera balloon atmosphere of H₂. Celite (5 g) was added to the reaction, thePd was filtered off and the filtrate was concentrated under reducedpressure to give 60 g (98%) of the saturated ester (Intermediate N2)which was used in the next step without further purification.

To a solution of LiAlH₄ (200 mL, 1 M in diethyl ether) at −78° C. underargon was added the unsaturated ester (Intermediate N2) in anhydrous THF(400 ml) in a slow stream with vigorous mechanical stirring. The mixturewas warmed to rt and additional THF (600 mL) was added. The reactionmixture was stirred for an additional 1 h. The mixture was cooled to 0°C. and quenched by the careful, consecutive addition of H₂O (7.60 ml),NaOH (7.60 ml of a 15% aqueous solution), and an additional portion ofH₂O (22.80 ml). The solids were filtered off and the filtrate wasconcentrated under reduced pressure. Subsequent purification bychromatography on SiO₂ with 20–50% EtOAc:hexanes gave 51 g (98%) of thealcohol (Intermediate N3) as a pale oil. To a solution of oxalylchloride (20.65 ml, 41.29 mmol) in anhydrous CH₂Cl₂ (100 ml) at −78° C.under argon was added dropwise a solution of DMSO (6.72 g, 86.0 mmol) inCH₂Cl₂ (25 ml). After mechanical stirring for 15 min. a solution of thealcohol (Intermediate N3, 6.40 g, 34.4 mmol) in CH₂Cl₂ (80 ml) was addeddropwise and the mixture was stirred an additional 15 min. at −78° C.before adding triethylamine (27.9 g, 275 mmol). The reaction was stirred2 h at 20° C. and then quenched with saturated aqueous NaHCO₃. Thismixture was extracted CH₂Cl₂ and the combined organic fractions werewashed consecutively with H₂O and brine, dried (MgSO₄) and concentratedunder reduced pressure. The resulting solids were purified bychromatography on SiO₂ with 20–30% EtOAc:hexanes to give 5.08 g, (79%)of the aldehyde (Intermediate N4) as a white solid. A solution of thealdehyde (Intermediate N4, 5.08 g, 27.59 mmol) in EtOH (40 ml) wastreated with tosylmethyl isocyanide (TosMIC) (5.15 g, 26.3 mmol) andNaCN (0.13 g, 2.68 mmol) at 20° C. for 3 h and then refrigerated. After2 h of refrigeration the solids were filtered off, dissolved inanhydrous MeOH, saturated with NH3 (30 ml) and heated in a sealed tubeat 100° C. for 3.5 h. The reaction was then concentrated under reducedpressure and the residues were taken up in CHCl₃, washed consecutivelywith saturated aqueous NaHCO₃ and brine, dried (MgSO₄) and concentratedto a red oil. This residue was further purified by chromatography onSiO₂ with 5–10% MeOH (saturated with NH3): CH₂Cl₂ to give 1.87 g (31%)of the imidazole derivative (Intermediate N5) as a pink oil. A solutionof Intermediate N5 (0.55 g, 2.48 mmol) in acetone (20 ml) containing HCl(5 N, 0.5 ml) was stirred for 5 h. The reaction was concentrated underreduced pressure, the residues were taken up in H₂O, neutralized to pH 7with saturated aqueous NaHCO₃ and extracted exhaustively withCHCl₃/isopropyl alcohol (3:1). The combined organic portions were washedconsecutively with H₂O and brine, dried (MgSO₄) and concentrated.Chromatography on SiO₂ with 5–10% MeOH (saturated with NH3): CH₂Cl₂ gave0.43 g (97%) of the desired ketone (Intermediate N6).

A solution of Intermediate N6 (0.20 g, 1.11 mmol) in anhydrous DMF (4ml) under argon was treated with triethylamine (0.14 g, 1.33 mmol) anddimethylsulfamoyl chloride (0.19 g, 1.33 mmol) under argon and stirred16 h. The solids were filtered off and the filtrate was concentrated atvia kugelrohr at 100° C. and 0.5 torr. The residues were taken up inCHCl₃ and washed consecutively with H₂O and brine, dried (MgSO₄) andconcentrated. Chromatography on SiO₂ with 1–5% MeOH:CH₂Cl₂ gave 0.22 g(69%) of the desired imidazole derivative (Intermediate N7) as a mixtureof regioisomers which were used in the next step without separation. Asolution of Intermediate N7 (0.18 g, 0.62 mmol) in anhydrous THF (10 ml)under argon was treated with methylmagnesium chloride (0.32 ml, 3.0 M inTHF) and the resulting mixture was stirred 16 h. The reaction wasquenched with a small amount of MeOH, concentrated under reducedpressure and the residues were taken up in H₂O. The mixture wasacidified by the dropwise addition of 1 N HCl until the solution washomogenous and then the pH was adjusted to 7 with saturated aqueousNaHCO₃. The organic materials were extracted into CHCl₃ and the combinedorganic portions were washed consecutively with H₂O and brine, dried(MgSO₄) and concentrated. Chromatography on SiO₂ with 5% MeOH:CH₂Cl₂gave 0.18 g (95%) of the cyclohexyl alcohol derivative (Intermediate N8)as a mixture of regioisomers which were carried on without separation. Asolution of Intermediate N8 (0.14 g, 0.46 mmol) in anhydrous benzene (3ml) at 0° C. under argon was treated with(methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt(Burgess reagent) (0.12 g, 0.51 mmol) and stirred 1 h at 20° C. Thereaction was concentrated under reduced pressure and subsequentpurification by chromatography on SiO₂ with 5% MeOH:CH₂Cl₂ gave 0.12 g(92%) of the alkenes Intermediates N9 and N10 as a mixture of isomerswhich were used in the next step without separation. The mixture ofisomers Intermediate N9 and N10 (0.12 g, 0.42 mmol) were refluxed in asolution composed of MeOH (2 ml) and KOH (2 ml of a 5 N solution) for 30h. The reaction was concentrated under reduced pressure and the residueswere taken up in H₂O and extracted exhaustively with CHCl₃. The combinedorganic portions were washed consecutively with H₂O and brine, dried(MgSO₄) and concentrated. Chromatography on SiO₂ with 5–10% MeOH(saturated with NH3): CH₂Cl₂ gave 0.05 g (67%) of alkenes IntermediatesN11 and N12 as a mixture of isomers which were used in the next stepwithout separation.

The mixture of alkenes Intermediates N11 and N12 (45 mg, 0.26 mmol) andp-toluenesulfonic acid hydrate (63 g, 0.32 mmol) were heated at refluxin 1,2-dichloroethane (2 ml) under argon for 20 h. The reaction wasconcentrated under reduced pressure and the residues were purified bychromatography on SiO₂ with 10% MeOH (saturated with NH3): CH₂Cl₂ togive the free base of imidazole derivative (Intermediate N13 as oneisomer. The imidazole (Intermediate N13) was recrystallized by stirringin MeOH or THF with an equimolar amount of fumaric acid until all solidshad disappeared followed by the addition of a small amount of diethylether and cold storage. The imidazole-fumaric acid salt was recovered aswhite crystals 40 mg (54%). This material was subjected to theapplicable process steps of Method A to obtain4-(4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 38):

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.54 (s, 1H), 5.34 (s, 1H), 2.39 (d, J=6.4Hz, 2H), 2.10–1.90 (m, 3H), 1.80–1.72 (m, 2H), 1.62 (s, 3H), 1.30–1.20(m, 1H).

EXAMPLE N-1 (COMPOUND 39)

4-(4-Ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 39) was prepared by using ethyl magnesium chloride instead ofmethyl magnesium chloride in the applicable step of Method N.

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.54 (s, 1H), 5.34 (brs, 1H), 2.41 (d,J=6.4 Hz, 2H), 2.02–1.92 (m, 5H), 1.78–1.72 (m, 3H), 1.31–1.20 (m, 1H),0.98 (t, J=7.5 Hz, 3H).

EXAMPLE O (COMPOUND 40) Procedure for the preparation of4-(4-ethynyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 40)

The alcohol (Intermediate 01, obtainable in accordance with thepublication Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016) (1.83g, 12.88 mmol), chlorotriethylsilane (TESCl, 2.14 g, 14.17 mmol), andEt₃N (1.43 g, 14.17 mmol) were stirred in THF (anhydrous, 50 ml) for 16h at 20° C. The resultant solution was taken up in Et₂O and washedconsecutively with 5% aqueous NH₄Cl, saturated aqueous NaHCO₃, H₂O,brine, dried (MgSO₄), filtered and concentrated under reduced pressure.Subsequent purification by chromatography on SiO₂ with 5–10%EtOAc:hexanes gave 3.26 g (99%) of the triethylsilyl protected ketoalcohol (Intermediate O2) as a pale oil.

To a solution of the keto alcohol (Intermediate O2, 3.38 g, 13.22 mmol)in THF (anhydrous, 50 ml) at 0° C. under argon was added ethynylmagnesium chloride (44.1 ml of a 0.5 M solution in THF). This mixturewas allowed to stir at 20° C. for 6 h and was then recooled to 0° C. andquenched with H₂O. The resultant solution was taken up in EtOAc andwashed consecutively with saturated aqueous NH₄Cl, saturated aqueousNaHCO₃, H₂O, brine, dried (MgSO₄), filtered and concentrated underreduced pressure. Subsequent purification by chromatography on SiO₂ with10–15% EtOAc:hexanes gave 2.99 g (80%) of the alcohol (Intermediate O3)as a pale oil.

To a solution of Intermediate O3 (2.94 g, 10.44 mmol) in THF (anhydrous,50 ml) at 0° C. under argon was added 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) (7.63 g, 50.12 mmol) and MeSO₂Cl (3.71 g, 32.36 mmol). Thismixture was allowed to stir at 20° C. for 20 h and was then recooled to0° C. and quenched with MeOH. The mixture was concentrated under reducedpressure and the residues were taken up in Et₂O and washed consecutivelywith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃ and brine, dried(MgSO₄) and concentrated under reduced pressure. The residues werepurified by chromatography on SiO₂ with 2% EtOAc:hexanes to give 0.88 gof the enyne (Intermediate O4) which was used in the next step withoutfurther purification.

The enyne (Intermediate O4, 0.88 g, 3.34 mmol) was stirred in a solutionof THF/AcOH/H₂O (4 ml in a ratio of 8:8:1) at 20° C. for 3 h. Themixture was concentrated under reduced pressure and the residues weretaken up in Et₂O and washed consecutively with saturated aqueous K₂CO₃,H₂O and brine, dried (MgSO₄) and concentrated under reduced pressure.The residues were purified by chromatography on SiO₂ with 30%EtOAc:hexanes to give 0.50 g of the alcohol (Intermediate O5) which wasused in the next step without further purification.

To a solution of oxalyl chloride (2 ml of a 2.0 M solution in CH₂Cl₂) inCH₂Cl₂ (anhydrous, 10 ml) at −78° C. under argon added DMSO (0.65 g,8.33 mmol) in CH₂Cl₂ (anhydrous, 5 ml) dropwise via cannula. Thereaction was stirred for 15 min. after addition was complete and thenthe alcohol (Intermediate O5, 0.50 g, 3.33 mmol) was added in CH₂Cl₂(anhydrous, 10 ml) dropwise via cannula and stirred for an additional 15minutes before adding neat Et₃N (2.70 g, 26.66 mmol). The reaction wasallowed to warm to 20° C. and stirred 2 h and then quenched withsaturated aqueous NaHCO₃. This mixture was extracted with CH₂Cl₂. andthe combined organic fractions were washed with H₂O and brine, dried(MgSO₄) and concentrated under reduced pressure. The residues werepurified by chromatography on SiO₂ with 15% EtOAc:hexanes to give 0.32 g(65%) of the aldehyde (Intermediate 06).

A solution of the aldehyde Intermediate O6 (0.38 g, 2.54 mmol) in EtOH(anhydrous, 1.5 ml) was treated with tosylmethyl isocyanide (TosMIC)(0.52 g, 2.67 mmol) and NaCN (0.013 g, 0.25 mmol) at 20° C. for 2 h.This mixture was concentrated under reduced pressure and the resultingresidue was taken up in MeOH saturated with NH₃ (anhydrous, 10 ml) andheated in a sealed tube at 100° C. for 3.5 h. The reaction was thenconcentrated under reduced pressure and purified by chromatography onSiO₂ with 10% MeOH:CH₂Cl₂ to give 0.16 g (35%) of the imidazolederivative (Intermediate O7) as an amber oil.

4-(4-Ethynyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 40) was prepared by subjecting the imidazole derivativeIntermediate 7 to the applicable process steps of Method A.

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.57 (s, 1H), 6.08 (brs, 1H), 3.10 (s,1H), 2.43 (d, J=6.4 Hz, 2H), 2.18–2.14 (m, 3H), 1.85–1.75 (m, 3H),1.30–1.25 (m, 1H).

EXAMPLE ONE Method ONE: Procedure for the Preparation of4-[(2-phenylcyclopent-2-en-1-yl)methyl]-1,3-dihydro-2H-imidazole-2-thione(Compound 112)

A solution of 2-bromo-cyclopent-2-enol (Intermediate D3) (21.7 g, 133.1mmol) in ethyl vinyl ether (300 mL) was treated with Hg(OAc)₂ (31.8 g,99 mmol) at rt for 60 h. The mixture was quenched with 5% NaOH (150 mL)and filtered through celite. The residue was concentrated to yield1-bromo-5-vinyloxy-cyclopentene as a pale yellow oil, 14.2 g (46%).1-Bromo-5-vinyloxy-cyclopentene (14.1 g, 74.4 mmol) in toluene washeated in a re-sealable tube at 130° C. for 24 h.(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE 1) wasisolated after flash chromatography on silica gel with hexanes to 5%ethyl acetate:hexanes, 10.4 g (74%).

(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) (1.85 g,9.32 mmol) in benzene (70 mL) was treated with Na₂CO₃ (14.0 mL, 2M inH₂O.) and phenylboronic acid (2.27 g, 18.6 mmol) in EtOH (40 mL).

Tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄ catalyst (1.61 g,1.40 mmol) was added and the mixture was heated to 80° C. for 3.5 h.until no starting material remained. The benzene was replaced withdiethyl ether and the mixture was filtered through celite. The filtratewas washed with sat. K₂CO₃, brine and dried over MgSO₄. Pure(2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) 1.07 g(62%) was isolated by chromatography on silica gel. Use of(2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) in Method A(without formation of the fumarate) produced4-[(2-phenylcyclopent-2-en-1-yl)methyl]-1,3-dihydro-2H-imidazole-2-thione(Compound 112).

¹H NMR (300 MHz, CDCl₃) δ 11.5 (s, 1H), 11.3 (s, 1H), 7.39–7.16 (m, 5H),6.32 (s, 1H), 6.07 (s, 1H), 3.46 (brs, 1H), 2.78 (dd, J=15.1, 3.4 Hz,1H), 2.43–2.28 (m, 3H), 2.10 (dd, J=13.2, 8.2 Hz, 1H) 1.82–1.67 (m, 1H).

EXAMPLE ONE-1 (COMPOUND 113)

Use of 4-methylphenylboronic acid (commercially available from Aldrich)in Method ONE produced4-[2-(4-methylphenyl)cyclopent-2-en-1-yl]methyl-1,3-dihydro-2H-imidazole-2-thione(Compound 113).

¹H NMR (300 MHz, CDCl₃) δ 11.6 (s, 1H), 11.5 (s, 1H), 7.33–7.12 (m, 4H),6.32 (s, 1H), 6.02 (s, 1H), 3.50–3.40 (m, 1H), 2.80–2.74 (m, 1H), 2.38(brs, 3H), 2.29 (s, 3H), 2.11–2.00 (m, 1H), 1.74–1.70 (m, 1H).

EXAMPLE ONE-2 (COMPOUND 114)

Use of 4-methoxyphenylboronic acid (commercially available from Aldrich)in Method ONE produced4-[2-(4-methoxyphenyl)cyclopent-2-en-1-yl]methyl-1,3-dihydro-2H-imidazole-2-thione(Compound 114).

¹H NMR (300 MHz, CDCl₃) δ 11.8 (s, H), 11.6 (s, 1H), 7.36 (d, J=9 Hz,2H), 6.85 (d, J=9 Hz, 2H), 6.33 (s, 1H), 5.95 (s, 1H), 3.75 (s, 3H),3.41 (brs, 1H), 2.82–2.78 (m, 1H), 2.36 (s, 1H), 2.35–2.30 (m, 2H),2.11–2.00 (m, 1H), 1.78–1.70 (m, 1H).

EXAMPLE ONE-3 (COMPOUND 115)

Use of 4-cyanophenylboronic acid (commercially available from Aldrich)in Method ONE produced4-[5-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-cyclopent-1-enyl]-benzonitrile(Compound 115).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.81–7.75 (m,4H), 6.55 (s, 1H), 6.50 (s, 1H), 3.41 (brs, 2H), 2.51–2.42 (m, 2H),2.16–1.95 (m, 2H), 1.76–1.74 (m, 1H).

EXAMPLE ONE-4 (COMPOUND 116)

Use of 3-nitrophenylboronic acid (commercially available from Aldrich)in Method ONE produced4-[2-(3-nitrophenyl)cyclopent-2-en-1-yl]methyl-1,3-dihydro-2H-imidazole-2-thione(Compound 116).

¹H NMR (300 MHz, CDCl₃) δ 12.1 (s, 1H), 11.5 (s, 1H), 8.20 (s, 1H), 7.96(d, J=12 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.47 (t, J=6 Hz, 1H), 6.41 (s,1H), 6.22 (s, 1H), 3.50 (brs, 1H), 2.76–2.70 (m, 1H), 2.45–2.30 (m, 3H),2.13–2.00 (m, 1H), 1.82–1.76 (m, 1H).

EXAMPLE TWO Method TWO: Procedure for the Preparation of(+)-4-[(S*)-2-(3-fluorophenyl)-2-cyclopent-2-enylmethyl-1,3-dihydro-imidazole-2-thione(Compound 117)

Use of (R)-2-methyl-oxazaborolidine catalyst (20 mol %) (commerciallyavailable from Aldrich) with BH₃.SMe₂ in the reduction of IntermediateD2 (see: Corey, E. J.; Chen C.-P.; Reichard, G. A. Tetrahedron Lett.1989, 30, 6275 and Xavier, L. C. et al; Organic Syntheses 1996, 74, 50incorporated herein by reference) produced(−)-(S)-2-bromo-cyclopent-2-enol (Intermediate TWO1). Use of opticallyenriched (−)-(S)-2-bromo-cyclopent-2-enol (Intermediate TWO1) andsubstituting 3-fluorophenylboronic acid (commercially available fromAldrich) in Method TWO produced(+)-4-[(S*)-2-(3-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 117).

opt. rotation [α]_(D) ²⁰+116.3° (c 2.45 in CHCl₃) ¹H NMR same asCompound 129 (see below)

EXAMPLE TWO-1 (COMPOUND 118)

Use of (R)-2-methyl-oxazaborolidine catalyst with BH₃.SMe₂ for thereduction step and substituting 4-fluorophenylboronic acid (commerciallyavailable from Aldrich) in Method TWO produced(+)-4-[(S*)-2-(4-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 118).

opt. rotation [α]_(D) ²⁰+90.00 (c 4.07 in MeOH)

Chiral HPLC isolation of Compound 118: From racemic Compound 123 (seeExample THREE) isolation of the 2^(nd) eluting enantiomer from thefollowing conditions: Chiral HPLC; 10% isopropyl alcohol/hexane at 1mL/m on a Chiralcel OJ 4.6×250 mm column; detector uv at 220 nm; rt;isocratic; collect 14.7 m (peak two). 96% ee; opt. rotation [α]_(D)²⁰+75° (c 1.03 in MeOH) ¹H NMR same as Compound 123 (see below)

EXAMPLE TWO-2 (COMPOUND 119)

Use of (R)-2-methyl-oxazaborolidine catalyst with BH₃.SMe₂ for thereduction step and substituting 3,5-difluorophenylboronic acid(commercially available from Aldrich) in Method TWO produced(+)-4-[(S*)-2-(3,5-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 119).

opt. rotation [α]_(D) ²⁰+87.8° (c 0.90 in MeOH) ¹H NMR same as compound126.

EXAMPLE TWO-3 (COMPOUND 120)

Use of (S)-2-methyl-oxazaborolidine catalyst (20 mol %) with BH3.SMe₂ inthe reduction of Intermediate D2 produced(+)-(R)-2-bromo-cyclopent-2-enol. Use of optically enriched(+)-(R)-2-bromo-cyclopent-2-enol and substituting 3-fluorophenylboronicacid (commercially available from Aldrich) in Method TWO produced(−)-4-[(R*)-2-(3-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 120).

opt. rotation [α]_(D) ²⁰−108.9 (c=1.24 in CHCl₃)

Chiral HPLC isolation of Compound 120: same as for Compound 18 (seeabove) collect 12.6 m (peak one). 99% ee; opt. rotation [α]_(D) ²⁰−86°(c 1.10 in MeOH).

¹H NMR same as Compound 129 (see below).

EXAMPLE TWO-4 (COMPOUND 121)

Use of (S)-2-methyl-oxazaborolidine catalyst with BH3-SMe₂ for thereduction step and substituting 4-fluorophenylboronic acid (commerciallyavailable from Aldrich) in Method TWO produced(−)-4-[(R*)-2-(4-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 121).

opt. rotation [α]_(D) ²¹−85.6° (c 1.24 in MeOH) ¹H NMR same as Compound123.

EXAMPLE TWO-5 (COMPOUND 122)

Use of (S)-2-methyl-oxazaborolidine catalyst with BH₃.SMe₂ for thereduction step and substituting 3,5-difluorophenylboronic acid(commercially available from Aldrich) in Method TWO produced(−)-4-[(R*)-2-(3,5-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 122).

opt. rotation [α]_(D) ²⁰−96.1° (c 1.32 in MeOH) ¹H NMR same as Compound126.

EXAMPLE THREE Method THREE: Procedure for Preparation of4-[2-(4-fluoro-phenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 123)

2-Bromo-cyclopent-2-enol (Intermediate D3) (1.1 g, 6.7 mmol) and the4-fluoroboronic acid (commercially available from Aldrich) (1.09 g, 7.8mmol) in dioxane (20 mL) was treated with 2M Na₂CO₃ (14 mL) anddegassed. Pd(PPh₃)₄ (0.4 g, ˜5 mol %) was added to the mixture anddegassed with N₂ gas for 15 m. The reaction mixture was heated to refluxfor one hour, cooled to rt and diluted with ether and water. The aqueouslayer was extracted with ether. The combined layers were washed withbrine and dried over Na₂SO₄. The suspension was filtered and freed ofsolvent. The residue was purified by chromatography on SiO₂ to give2-(4-flourophenyl)-cyclopent-2-enol (Intermediate THREE1).

Use of 2-(4-flourophenyl)-cyclopent-2-enol (Intermediate THREE1) inMethod A produced4-[2-(4-fluoro-phenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 123).

¹H NMR (500 MHz, CDCl₃) δ 11.3 (s, 1H), 11.1 (s, 1H), 7.42–7.38 (m, 2H),7.06–7.00 (m, 2H), 6.37 (s, 1H), 6.025 (s, 1H), 3.43 (s, 1H), 2.79–2.72(m, 1H), 2.42–2.29 (m, 3H), 2.16–2.08 (m, 1H), 1.78–1.76 (m, 1H).

EXAMPLE THREE-1 (COMPOUND 124)

Use of 3,4-difluorophenylboronic acid (commercially available fromAldrich) in Method THREE produced4-[2-(3,4-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 124).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.41–7.34 (m, 1H), 7.24–7.15 (m, 2H), 6.49(s, 1H), 6.15 (s, 1H), 3.40 (brs, 1H), 2.73–2.68 (m, 1H), 2.48–2.42 (m,2H), 2.35–2.27 (m, 1H), 2.20–2.05 (m, 1H), 1.90–1.78 (m, 1H).

EXAMPLE THREE-2 (COMPOUND 125)

Use of 5-chlorothiophene-2-boronic acid (commercially available fromAldrich) in Method THREE produced4-[2-(5-chloro-thiophen-2-yl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 125).

¹H NMR (300 MHz, MeOD-d⁴) δ 6.84 (s, 2H), 6.52 (s, 1H), 5.96 (s, 1H),3.29 (brs, 1H), 2.82–2.76 (m, 1H), 2.44–2.36 (m, 3H), 2.14–2.00 (m, 1H),1.86–1.77 (m, 1H).

EXAMPLE FOUR Method FOUR: Procedure for the Preparation of4-[2-(3,5-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 126)

2-Bromo-cyclopent-2-enol (Intermediate D3) (2.18 g, 13.4 mmol) andN,N-dimethylacetamide dimethyl acetal (3.5 mL, 21.5 mmol) in m-xylene(˜20 mL) were heated to 140° C. for 14 h. The mixture was freed ofsolvent and the residue was purified on a column of silica gel with 30%to 50% EtOAc:hexanes to give2-(2-bromo-cyclopent-2-enyl)-N,N-dimethyl-acetamide (Intermediate FOUR1)1.95 g (63%) as a brown oil.

2-(2-Bromo-cyclopent-2-enyl)-N,N-dimethyl-acetamide (Intermediate FOUR1)(1.16 g, 5 mmol) in benzene (36 mL), and Na₂CO₃ (5 mL, 2M) was treatedwith a solution of 3,5-difluoroboronic acid (1.1 g, 6.96 mmol) in EtOH(25 mL). Tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄] (0.3 g, 5mol %) was added and the degassed mixture was heated to 80° C. for 1.5h. The mixture was diluted with water and extracted with diethyl ether(2×). The combined organic layers were dried over MgSO₄, filtered andevaporated to dryness. The oil was purified by column chromatography onsilica gel with 40% EtOAc:hexane to give2-[2-(3,5-difluoro-phenyl)-cyclopent-2-enyl]-N,N-dimethyl-acetamide 0.93g (70%) as a light yellow solid. This amide was reduced with DIBAL (14.2mL, 1M in hexane) in Et₂O:THF (5:1) (60 mL) at −78° C. over 1.5 h. Themixture was subjected to an aqueous work-up with Rochelle's saltsolution. The aldehyde,2-(3,5-difluoro-phenyl)-cyclopent-2-enyl]-acetaldehyde (IntermediateFOUR2) was isolated in an approximate yield of 70%.

Use of Intermediate FOUR2 and 3,5-difluorophenylboronic acid(commercially available from Aldrich) in Method A produced4-[2-(3,5-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 126).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.11–7.08 (m, 2H), 6.82–6.77 (m, 1H), 6.26(s, 1H), 3.40 (brs, 1H), 2.72–2.69 (m, 1H), 2.49–2.41 (m, 2H), 2.34–2.29(m, 1H), 2.16–2.08 (m, 1H), 1.84–1.79 (m, 1H).

EXAMPLE FIVE Method FIVE: Procedure for the Preparation of4-[2-(2-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 127)

2-(2-Bromo-cyclopent-2-enyl)-N,N-dimethyl-acetamide (Intermediate FOUR1)(1.93 g, 8.3 mmol) in THF (50 mL) was reacted with lithiumtriethylborohydride (19 mL, 1 M in THF) at 0° C. for 1 h. The mixturewas treated with an aqueous work-up and the resultant alcohol waspurified by column chromatography to give 0.92 g of2-(2-bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1.

2-(2-Bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1 (1.21 g, 6.33mmol) in benzene (40 mL), and Na₂CO₃ (7 mL, 2M) was treated with asolution of 2-fluorophenylboronic acid (1.08 g, 7.72 mmol) in EtOH (28mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄ (0.38 g, 5 mol%) was added and the mixture was heated to 80° C. for 1.5 h. The mixturewas diluted with water and extracted with diethyl ether (2×). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedto dryness. The oil was purified by column chromatography on silica gelwith 30% EtOAc:hexane to give2-[2-(2-fluoro-phenyl)-cyclopent-2-enyl]-ethanol Intermediate FIVE2(1.21 g).

The alcohol Intermediate FIVE2 (1.2 g, 5.87 mmol) in acetonitrile (20mL) was mixed with 4 Å molecular sieves (1.21 g), 4-methylmorpholine-N-oxide (1.38 g, 11.8 mmol) and TPAP: tetrapropylammoniumperruthenate (0.22 g, 10 mol % catalyst) at rt for 1 h. The aldehyde,[2-(2-fluoro-phenyl)-cyclopent-2-enyl]-acetaldehyde (Intermediate FIVE3)was purified on a column of silica gel eluted with 10% EtOAc:Hexane(˜25%).

Use of [2-(2-fluoro-phenyl)-cyclopent-2-enyl]-acetaldehyde (IntermediateFIVE3) in Method A produced4-[2-(2-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 127).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.41–7.36 (m, 1H), 7.27–7.20 (m, 1H),7.16–7.63 (m, 2H), 6.42 (s, 1H), 6.15 (s, 1H), 3.52 (m, 1H), 2.67–2.60(m, 1H), 2.52–2.37 (m, 2H), 2.34–2.26 (m, 1H), 2.21–2.08 (m, 1H),1.80–1.69 (m, 1H).

EXAMPLE SIX Method SIX: Procedure for the Preparation of4-[2-(2,4-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 128)

A mixture of two compounds:4-[2-(2,4-difluoro-phenyl)-cyclopent-2-enylmethyl]-1H-imidazole and4-(2-bromo-cyclopent-2-enylmethyl)-1H-imidazole (Intermediate SIX1)(produced with procedures as in Method FIVE, but without completecoupling of the boronic acid) were subjected to the reaction found inMethod P. The mixture, Intermediate SIX2 was subjected to the couplingreaction as follows. Intermediate SIX2 (0.25 g, ˜1.1 mmol) in benzene (8mL), and Na₂CO₃ (1 mL, 2M) was treated with a solution of2,4-difluoroboronic acid (commercially available from Aldrich) (0.31 g)in EtOH (6 mL). Tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₄ (˜5mol %) was added and the mixture was heated to 80° C. for 3 h. Themixture was diluted with water and extracted with diethyl ether (2×).The combined organic layers were dried over MgSO₄, filtered andevaporated to dryness. The oil was purified by column chromatography onsilica gel with 30% EtOAc:hexane to give Intermediate SIX3 (0.14 g).

Finally, Intermediate SIX3 was converted to the thione compound by useof Lawesson's reagent in the standard fashion as follows. IntermediateSIX3 (0.14 g, 0.5 mmol) and Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](commercially available from Aldrich) (0.45 g, ˜1.1 mmol) in dioxanewere heated at reflux for several hours. The mixture was poured ontosilica gel and the solvent was removed under vacuum. The crude materialwas placed onto a column of silica and the product was eluted with 4%NH₃—MeOH: CH₂Cl₂. This method produced4-[2-(2,4-difluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 128).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.44–7.36 (m, 1H), 6.95–6.88 (m, 2H), 6.42(s, 1H), 6.12 (s, 1H), 3.47 (brs, 1H), 2.64–2.58 (m, 1H), 2.51–2.44 (m,2H), 2.35–2.26 (m, 1H), 2.20–2.08 (m, 1H), 1.79–1.69 (m, 1H).

EXAMPLE SEVEN Method SEVEN: Procedure for the Preparation of Produced4-[2-(3-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 129)

(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) wastransformed via reactions as described in Method P to4-(2-bromo-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one(IntermediateSEVEN1). Intermediate SEVEN1 was processed according toMethod SIX into4-[2-(3-fluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 129).

¹H NMR (500 MHz, MeOD-d⁴) δ 7.35–7.30 (m, 1H), 7.27 (d, J=8.5 Hz, 1H),7.21 d, J=10.5 Hz, 1H), 6.97–6.93 (m, 1H), 6.49 (s, 1H), 6.19 (s, 1H),3.43 (brs, 1H), 2.73–2.70 (m, 1H), 2.50–2.40 (m, 2H), 2.33–2.28 (m, 1H),2.17–2.09 (m, 1H), 1.84–1.78 (m, 1H).

EXAMPLE EIGHT Method EIGHT: Procedure for the Preparation of4-[2-(2,5-difluorofluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 130)

Use of 2,5-difluorophenylboronic acid (commercially available fromAldrich) in Method THREE produced2-(2,5-difluoro-phenyl)-cyclopent-2-enol (Intermediate EIGHT1). Use ofprocedures in Method ONE and Method A produced4-[2-(2,5-difluorofluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 130).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.17–7.10 (m, 1H), 7.09–7.02 (m, 1H),6.98–6.91 (m, 1H), 6.44 (s, 1H), 6.26 (s, 1H), 3.47 (brs, 1H), 2.66–2.60(m, 1H), 2.51–2.42 (m, 2H), 2.34–2.26 (m, 1H), 2.18–2.05 (m, 1H),1.78–1.69 (m, 1H).

EXAMPLE EIGHT-1 (COMPOUND 131)

Use of thiophene-2-boronic acid (commercially available from Aldrich) inMethod EIGHT produced4-[2-thiophen-2-yl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 131).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.22 (d, J=5.1 Hz, 11H), 7.05 (d, J=3.6 Hz,1H), 6.99–6.96 (m, 1H), 6.49 (s, 1H), 5.98 (s, 1H), 3.30 (brs, 1H),2.85–2.80 (m, 1H), 2.44–2.37 (m, 3H), 2.14–2.01 (m, 1H), 1.85–1.77 (m,1H).

EXAMPLE NINE Method NINE: Procedure for the Preparation of Produced4-[3-ethyl-2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 132)

3-Ethoxy-cyclopent-2-enone (Intermediate NINE1) (commercially availablefrom Aldrich) (10.0 g, 77.6 mmol) in carbon tetrachloride (15 mL) at 0°C. was treated with NBS (15.3 g, ˜85 mmol) added portion-wise over 30 m.After 1 h at 0° C. the mixture was partitioned between CH₂Cl₂ andsaturated NaHCO₃. The aqueous layer was extracted with CH₂Cl₂. Thepooled organic layers were washed with H₂O (2×) and dried over MgSO₄.The mixture was filtered and evaporated to dryness. The solid wasrecrystallized from pentane:ether to give 13.3 g of2-bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2).

2-Bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2) (10.5 g, 51.2mmol) and K₂CO₃ (14.2 g, 102 mmol) in toluene (100 mL), benzene (100 mL)and H₂O (50 mL) was treated with a solution of 4-fluorophenylboronicacid (9.31 g, 66.5) in EtOH (100 mL).Tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₄ (3 g, 2.6 mmol),bis(dibenzylideneacetone)palladium(0), Pd₂(dba)₃ (0.47 g, 0.5 mmol) andtriphenylphosphine (0.27 g, 1.0 mmol) were added and the mixture waspurged with N₂ for 15 m. The mixture was heated to 100° C. for 15 h. Themixture was diluted with water and EtOAc:hexane. After extracting withEtOAc:hexane, the combined organic layers were dried over MgSO₄,filtered and evaporated to dryness. The crude oil was purified by columnchromatography on silica gel with 2.5% EtOAc:CH₂Cl₂ to give3-ethoxy-2-(4-fluoro-phenyl)-cyclopent-2-enone (Intermediate NINE3) 7.85g (70%).

Cerium chloride.7H₂O was dried under vacuum (˜1 Torr) with gradualheating to 140° C. The cerium chloride.nH₂O (3.6 g, 13.6 mmol) was driedfurther under vacuum with heating to 170° C. over 3 h. The material wascooled to rt and suspended in THF (20 mL). Stirring was continued for 2h. 3-Ethoxy-2-(4-fluoro-phenyl)-cyclopent-2-enone (Intermediate NINE3)(2.0 g, 9.1 mmol) in THF (˜20 mL) was added to this mixture. Thereaction mixture was cooled to 0° C. and ethyl magnesium bromide(commercially available from Aldrich) (13 mL, 39 mmol, 3M in ether) wasadded dropwise. The mixture was warmed to rt and allowed to stir for 15h. The whole was cooled to 0° C. and quenched by the addition of 2% HCl(100 mL) and stirred for 15 m. The mixture was extracted with EtOAc andthe combined organic layers were evaporated to give the crude oil thatwas used in the next step without further purification. The reductionwith NaBH₄ was performed as in Method A to yield Intermediate NINE4.

Use of 3-ethyl-2-(4-fluoro-phenyl)-cyclopent-2-enol of (IntermediateNINE4) in Method A produced4-[3-ethyl-2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 132).

¹H NMR (300 MHz, CDCl₃) δ 11.4 (s, 1H), 11.2 (s, 1H), 7.16–7.10 (m, 2H),7.02–6.96 (m, 2H), 6.03 (s, 1H), 3.37 (brs, 1H), 2.61–2.01 (series of m,7H), 1.58–1.49 (m, 1H), 0.97 (t, J=8.4 Hz, 3H).

EXAMPLE NINE-1 (COMPOUND 133)

Use of n-propyl magnesium chloride (commercially available from Aldrich)in Method NINE produced4-[2-(4-fluoro-phenyl)-3-propyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 133).

¹H NMR (300 MHz, CDCl₃) δ 11.5 (s, 1H), 11.3 (s, 1H), 7.12 (dd, J=5.7,8.7 Hz, 2H), 6.99 (t, J=8.4 Hz, 2H), 6.30 (s, 1H), 3.37 (brs, 1H),2.61–2.54 (m, 1H), 2.47–2.01 (m, 6H), 1.59–1.47 (m, 1H), 1.45–1.32 (m,2H), 0.81 (t, J=7.5 Hz, 3H).

EXAMPLE NINE-2 (COMPOUND 134)

Use of isopropyl magnesium chloride (commercially available fromAldrich) in Method NINE produced4-[2-(4-fluoro-phenyl)-3-isopropyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 134).

¹H NMR (300 MHz, CDCl₃) δ 11.6 (s, 1H), 11.4 (s, 1H), 7.11 (dd, J=5.7,8.7 Hz, 2H), 6.98 (t, J=8.7 Hz, 2H), 6.30 (s, 1H), 3.33 (brs, 1H),2.71–2.50 (m, 2H), 2.38–2.30 (m, 2H), 2.20–1.99 (m, 2H), 1.55–1.44 (m,1H), 1.05 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H).

EXAMPLE NINE-3 (COMPOUND 135)

Use of cyclopropyl magnesium bromide (made from cyclopropyl bromide(commercially available from Aldrich) and Mg(0)) in Method NINE produced4-[3-cyclopropyl-2-(4-fluoro-phenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 135).

¹H NMR (300 MHz, MeOD-d⁴) δ 7.32 (dd, J=6.0, 9.0 Hz, 2H), 7.07 (t, J=8.7Hz, 2H), 6.38 (s, 1H), 3.39 (brs, 1H), 2.58–2.52 (m, 1H), 2.23–2.01 (m,4H), 1.68–1.49 (series of m, 2H), 0.73–0.66 (m, 1H), 0.60–0.51 (m, 3H).

EXAMPLE NINE-4 (COMPOUND 136)

Use of 3-ethoxy-cyclohex-2-enone as the starting material and methylmagnesium bromide (both commercially available from Aldrich) in MethodNINE produced4-[2-(4-fluoro-phenyl)-3-methyl-cyclohex-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 136).

¹H NMR (300 MHz, CDCl₃) δ 7.10–6.90 (m, 4H), 6.30 (s, 1H), 2.66 (brs,1H), 2.42–2.21 (m, 2H), 2.14–2.04 (m, 2H), 1.71–1.57 (m, 4H), 1.49 (s,3H).

EXAMPLE TEN Method TEN: Procedure for the Preparation of Produced4-[2-methyl-5-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl)cyclopent-1-enyl]benzonitrile(Compound 137)

2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TEN1) (commerciallyavailable from Aldrich) (2.04 g, 11.4 mmol) and K₂CO₃ (3.16 g in 11 mLH₂O) in toluene (45 mL) was treated with a solution 4-cyanophenylboronicacid (commercially available from Aldrich) (2.2 g, 15 mmol) in EtOH (27mL). Tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₄ (0.4 g),bis(dibenzylideneacetone)palladium(0), Pd₂(dba)₃ (0.055 g, ˜5 mol %) andtriphenylphosphine (0.4 g) were added and the mixture was purged with N₂for 15 m. The mixture was heated to 80° C. for 15 h. The mixture wasdiluted with water and EtOAc:hexane. After extracting with EtOAc:hexane,the combined organic layers were dried over MgSO₄, filtered andevaporated to dryness. The crude oil was purified by columnchromatography on silica gel with CH₂Cl₂ to give4-(2-methyl-5-oxo-cyclopent-1-enyl)-benzonitrile (Intermediate TEN2)1.74 g.

Use of 4-(2-methyl-5-oxo-cyclopent-1-enyl)-benzonitrile (IntermediateTEN2) in Method A produced4-[2-methyl-5-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl)cyclopent-1-enyl]benzonitrile(Compound 137).

¹H NMR (500 MHz, MeOD-d⁴) δ 7.70 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz,2H), 6.38 (s, 1H), 3.50 (brs, 1H), 2.61–2.52 (m, 2H), 2.45–2.13 (seriesof m, 3H), 1.78 (s, 3H), 1.68–1.61 (m, 1H).

EXAMPLE TEN-1 (COMPOUND 138)

Use of 4-nitrophenylboronic acid (commercially available from Aldrich)in Method TEN produced4-[3-methyl-2-(nitro-phenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 138).

¹H NMR (300 MHz, CDCl₃) δ 11.6 (s, 1H), 10.8 (s, 1H), 8.17 (d, J=8.7 Hz,2H), 7.39 (d, J=9.0 Hz, 2H), 6.35 (s, 1H), 3.54 (brs, 1H), 2.64–2.09 (m,5H), 1.78 (s, 3H), 1.64–1.53 (m, 1H).

EXAMPLE TEN-2 (139)

Use of 3,5-difluorophenylboronic acid (commercially available fromAldrich) in Method TEN produced4-[2-(3,5-difluorophenyl)-3-methyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 139).

¹H NMR (300 MHz, CDCl₃) δ 11.0 (s, 1H), 10.6 (s, 1H), 6.77–6.63 (m, 3H),6.32 (s, 1H), 3.40 (brs, 1H), 2.65–2.05 (series of m, 5H), 1.76 (s, 3H),1.61–1.50 (s, 1H).

EXAMPLE TWELVE Method TWELVE: Procedure for the Preparation of4-[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 140)

2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TWELVE1) (commerciallyavailable from Aldrich) was homologated according to Method A to produce(2-bromo-3-methyl-cyclopent-2-enyl)-acetaldehyde (Intermediate TWELVE2).

(2-Bromo-3-methyl-cyclopent-2-enyl)-acetaldehyde (Intermediate TWELVE2)(7.28 mmol) in benzene (50 mL) was treated with Na₂CO₃ (7.3 mL, 2Msoln.) and 4-fluorophenylboronic acid (1.4 g, 10.0 mmol) in EtOH (35mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄ catalyst (0.54g, ˜5 mol %) was added and the mixture was heated to 80° C. for 15 h.until no starting material remained. The mixture was filtered throughcelite. The filtrate was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc and the organic layers werecombined and dried over MgSO₄. Chromatography on silica gel with 20%EtOAc:hexane delivered[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enyl]-acetaldehyde(Intermediate TWELVE3) 0.8 g.

[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enyl]-acetaldehyde(Intermediate TWELVE3) in Method A produced4-[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione(Compound 140).

¹H NMR (500 MHz, MeOD-d⁴) δ 7.22 (dd, J=5.5, 9.0 Hz, 2H), 7.06 (t, J=9.0Hz, 2H), 6.04 (s, 1H), 3.39 (brs, 1H), 2.56–2.46 (m, 2H), 2.38–2.32 (m,1H), 2.22–2.17 (m, 1H), 2.13–2.06 (m, 1H), 1.75 (s, 3H), 1.62–1.56 (m,1H).

EXAMPLE SIXTEEN-ALPHA (COMPOUND 141) Procedure for the Synthesis of8-chloro-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 141)

A mixture of CuCl₂ (2.0, 14.8 mmol) and t-butyl nitrite (2.3 mL, 17.4mmol) in acetonitrile (30 mL) at 65° C. was treated with8-amino-3,4-dihydro-2H-naphthalen-1-one (Intermediate J3) inacetonitrile (15 mL) over 10 m. The mixture was concentrated onto silicagel and purified by column chromatography with 10% EtOAc:hexane to give8-chloro-3,4-dihydro-2H-naphthalen-1-one (Intermediate SIXTEENalpha-1).Use of 8-chloro-3,4-dihydro-2H-naphthalen-1-one (IntermediateSIXTEENalpha-1) in Method E (note: PtO₂ was used as a substitute forPd/C as described in Method E) produced8-chloro-2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 141).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.42–7.32 (m, 2H), 7.24 (d, J=6.3 Hx, 1H),6.61 (s, 1H), 3.10–3.03 (m, 3H), 2.92–2.82 (m, 1H), 2.63 (dd, J=7.8, 7.2Hz, 1H), 2.20–2.12 (m, 1H), 1.85–1.71 (m, 1H).

EXAMPLE SIXTEENbeta Procedure for the Synthesis of 7-iodo-indan-1-one(Intermediate SIXTEENbeta3)

Use of indan-4-ylamine (Intermediate SIXTEEN-beta-1) (commerciallyavailable from Aldrich) in Method J produced 7-amino-indan-1-one(Intermediate SIXTEENbeta-2). A mixture of 7-amino-indan-1-one(Intermediate SIXTEENbeta-2) (1.44 g, 9.8 mmol) in water (11 mL), aceticacid (11 mL), and HCl (2.7 mL) was treated with a solution of NaNO₂(0.75 g in 2.8 mL) at 0° C. A solution of KI in water (1.76 g 10.4 mmolin 2.8 mL) was added and the mixture was heated to 60° C. for 1 h. Themixture was cooled and quenched with solid NaHSO₃ followed by water. Theproduct was extracted with CH₂Cl₂ (3×) and washed with sat. NaHCO₃ andbrine. The compound was purified by column chromatography on silica gelwith 60 to 70% CH₂Cl₂:hexane. 7-Iodo-indan-1-one (IntermediateSIXTEENbeta3) was isolated as a light yellow solid (31%).

EXAMPLE SEVENTEEN (COMPOUND 142) Procedure for the Synthesis Produced4-indan-2-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 142)

Use of indan-2-yl-acetic acid (commercially available from Lancaster)(Intermediate SEVENTEEN-1) (1.58 g, 8.88 mmol) in THF (15 mL) was addeddropwise to a solution of LiAlH₄ (9 mL, 1M in Et₂O) in THF (10 mL) at 0°C. The mixture was reacted for 2 h at rt and quenched with Rochelle'ssalt solution and extracted with Et₂O (3×). The organic layer was driedover MgSO₄, filtered and concentrated under vacuum. The alcohol (1.35 g,94%) was used in the next step without further purification. A solutionof 2-indan-2-yl-ethanol (1.35 g, 8.32 mmol) in 18 mL of CH₂Cl₂ and CH₃CN(2 mL) was treated with 4 Å molecular sieves (4.2 g)N-methylmorpholine-N-oxide (1.5 g, 13.5 mmol) and TPAP:tetra-n-propylammonium perruthenate (VII) (commercially available fromAldrich) (0.3 g, 0.85 mmol). The mixture was stirred for 16 h at rt. Themixture was poured directly onto a column of silica gel and eluted with10% EtOAc:hexane. To give indan-2-yl-acetaldehyde (IntermediateSEVENTEEN-2), 1.25 g (˜90%). Indan-2-yl-acetaldehyde (IntermediateSEVENTEEN-2) in Method A produced4-indan-2-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 142).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.16–7.12 (m, 2H), 7.10–7.06 (m, 2H), 6.59(s, 1H), 3.02 (dd, J=7.8, 7.2 Hz, 1H), 2.76–2.57 (m, 5H).

EXAMPLE SEVENTEEN-1 (COMPOUND 143)

Use of indan-2-carboxylic acid (commercially available from TCI America)in Method SEVENTEEN produced 4-indan-2-yl-1,3-dihydro-imidazole-2-thione(Compound 144).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.21 (m, 2H), 7.14–7.11 (m, 2H), 6.58 (s,1H), 3.55–3.44 (m, 1H), 3.29–3.20 (m, 2H), 3.03–2.92 (m, 2H)

EXAMPLE SEVENTEEN-2 (COMPOUND 144)

Use of 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (commerciallyavailable from Aldrich) in Method SEVENTEEN produced4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-1,3-dihydro-imidazole-2-thione(Compound 144).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.06 (brs, 4H), 6.54 (s, 1H), 3.09–3.03 (m,1H), 2.96–2.78 (m, 4H), 2.19–2.13 (m, 1H), 1.86–1.73 (m, 1H).

EXAMPLE EIGHTEEN (COMPOUND 145) Procedure for the Preparation of4-(5-fluoro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 145)

To a mixture of NaH (2.64 g, 66 mmol) in dimethylcarbonate (4.2 mL, 50mmol) in THF (30 mL) was added a solution of 5-fluoroindanone(commercially available from Aldrich) (5 g, 33 mmol). After 30 m at 65°C. the mixture was cooled to rt, acidified with HCl (aq) and extractedwith Et₂O or EtOAc. The organic layers were washed with water, driedover MgSO₄ and evaporated to dryness. The residue was used in the nextstep without further purification. The keto-ester was dissolved in AcOH(100 mL) and 70% perchloric acid (2 mL). 10% Pd/C (2 g) was added andthe mixture was hydrogenated at 50 psi for 18 h. The mixture was dilutedwith Et₂O or CHCl₃ and water and filtered through a pad of celite. Theorganic layer was separated and the aqueous layer was extracted withEt₂O. The organic fractions were pooled, washed with water, dried overMgSO₄, filtered and evaporated to leave a residue. The residue waspurified by chromatography on silica gel with 15% EtOAc: hexane to give5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate EIGHTEEN-3),2.25 g. Use of 5-fluoro-indan-2-carboxylic acid methyl ester(Intermediate EIGHTEEN-3) in Method SEVENTEEN produced4-(5-fluoro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 145).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.20 (dd, J=5.7,8.4 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 6.59 (s,1H), 3.42 (t, J=8.7 Hz, 1H), 3.18–3.07 (m, 2H), 2.94–2.81 (m, 2H).

EXAMPLE EIGHTEEN-1 (COMPOUND 146)

Use of 7-methyl-indan-1-one (commercially available from Aldrich) inMethod EIGHTEEN produced4-(4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 146).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.6 (s, 1H), 7.02–7.00 (m,2H), 6.94–6.92 (m, 1H), 6.60 (s, 1H), 3.43–3.32 (m, 1H), 3.18–3.07 (m,2H), 2.93–2.76 (m, 2H), 2.19 (s, 3H).

EXAMPLE EIGHTEEN-2 (COMPOUND 147)

Use of 6-methyl-indan-1-one (commercially available from Aldrich) inMethod EIGHTEEN produced4-(5-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 147).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.6 (s, 1H), 7.07 (d, J=7.2Hz, 1H), 7.01 (s, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.58 (s, 1H), 3.38–3.29(m, 1H), 3.12–3.04 (m, 2H), 2.89–2.80 (m, 2H), 2.24 (s, 3H).

EXAMPLE NINETEEN (COMPOUND 148) Procedure for the Preparation of4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148)

Use of 5-bromo-indan-1-one (Intermediate NINETEEN-1) in a reaction withNaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN)produced 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester(Intermediate NINETEEN-2). A solution of5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7 mmol)in TFA (80 mL) at 0° C. was treated with triethylsilane (TES) (17.0 mL,6.0 eq) and stirred for 18 h. After evaporation of the solvent, theresidue was diluted with Et₂O and washed with H₂O (5×100 mL), sat.NaHCO₃ (3×50 mL), brine (1×75 mL) and dried over MgSO₄ to give crude5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3).A solution of 5-bromo-indan-2-carboxylic acid methyl ester (IntermediateNINETEEN-3) in AcOH containing 20% HCl was stirred overnight. Afterevaporation of the solvent, the residue was dissolved in 1N NaOH. Theresulting mixture was washed with Et₂O (3×75 mL) after which it wasacidified with HCl (aq). The solution was extracted with CH₂Cl₂ (3×150mL) and the combined organic extracts was washed with H₂O (3×100 mL),brine (1×75 mL), dried over MgSO₄ and concentrated to give crude5-bromo-indan-2-carboxylic acid. Use of 5-bromo-indan-2-carboxylic acidin Method EIGHTEEN produced4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.41 (s, 1H),7.30 (d, J=8.1 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 6.60 (s, 1H), 3.46–3.35(m, 1H), 3.19–3.06 (m, 2H), 2.95–2.81 (m, 2H).

EXAMPLE NINETEEN-1 (COMPOUND 149)

4-Bromo-indan-1-one was obtained by the following procedure: A solutionof 3-(2-bromo-phenyl)-propionic acid (commercially available fromOakwood Products) (15.0 g, 65.5 mmol) in CH₂Cl₂ at 0° C. was reactedwith oxalyl chloride (7.2 mL, 1.5 eq) followed by 2–3 drops of DMF. Themixture was stirred until no more gas evolution was observed. As themixture was concentrated and the residue was dissolved in CH₂Cl₂, cooledto 0° C., and treated with AlCl₃ (9.6 g, 1.1 eq). After 1 h the mixturewas quenched with water and the layers were separated. The aqueous layerwas extracted with Et₂O (3×150 mL) and the combined organic extractswere washed with H₂O (3×100 mL), saturated NaHCO₃ (3×100 mL), brine(1×100 mL), dried over MgSO₄ and concentrated. 4-Bromoindan-1-one, 10.5g (76%) was obtained by chromatography using 10% EtOAc:hexane as eluant.Use of 4-bromo-indan-1-one in Method NINETEEN produced4-(4-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 149).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.34 (d, J=7.8Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.63 (s, 1H),3.50–3.40 (m, 1H), 3.30–3.12 (m, 2H), 3.06–2.85 (m, 2H).

EXAMPLE NINETEEN-2 (COMPOUND 150)

Use of 2,5-dimethylcinnamic acid in Method TWENTY (refer to ExampleTWENTY-4) produced 4,7-dimethyl-1-indanone. Use of4,7-dimethyl-1-indanone in Method NINETEEN produced4-(4,7-dimethyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound150)

¹H NMR (300 MHz, MeOH-d⁴) δ 6.85 (s, 2H), 6.59 (s, 1H), 3.55–3.45 (m,1H), 3.30–3.19 (m, 2H), 2.90–2.80 (m, 2H), 2.19 (s, 6H).

EXAMPLE NINETEEN-3 (COMPOUND 151)

Use of 5-chloro-indan-1-one (commercially available from Aldrich) inMethod NINETEEN produced4-(5-chloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 151).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.22–7.12 (m, 3H), 6.59 (s, 1H), 3.60–3.49(m, 1H), 3.27–3.19 (m, 2H), 3.02–2.91 (m, 2H).

EXAMPLE NINETEEN-4 (COMPOUND 152)

Thionyl chloride (10.0 mL, 1.5 eq) and 3-chloro-2-methyl-benzoic acid(commercially available from Aldrich) (15.6 g, 91.4 mmol) in benzene wasrefluxed until no more gas evolution was observed. After cooling to rtthe mixture was concentrated. The concentrate was diluted withdichloroethane and added to a solution of AlCl₃ (12.2 g, 1.0 eq) indichloroethane at 10–20° C. Ethylene was bubbled through the mixture for4 h. and the mixture was stirred overnight. The mixture was quenchedwith 4 N HCl. The resulting layers were separated and the aqueous layerwas extracted with Et₂O (3×250 mL). The combined organic extract waswashed with H₂O (3×150 mL), saturated NaHCO₃ (3×150 mL), brine (1×150mL), dried over MgSO₄ and concentrated. Concentrated sulfuric acid wasadded and the mixture was stirred at 85° C. for 1 h. After cooling tort, the reaction mixture was quenched with ice-water. The mixture wasextracted with Et₂O (3×250 mL) and the combined organic extracts werewashed with H₂O (3×200 mL), saturated NaHCO₃ (3×200 mL), brine (1×100mL), dried over MgSO₄ and concentrated. Pure6-chloro-7-methyl-1-indanone (11.9 g, 72%) was obtained after columnchromatography using 20% EtOAc:hexane as eluant. Use of6-chloro-7-methyl-1-indanone in Method NINETEEN produced4-(5-chloro-4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione(Compound 152).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.16 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz,1H), 6.62 (s, 1H), 3.59–3.52 (m, 1H), 3.31–3.24 (m, 2H), 3.00–2.92 (m,2H), 2.30 (s, 3H).

EXAMPLE NINETEEN-5 (COMPOUND 153)

Thionyl chloride (5.73 mL, ˜79 mmol) and 2,3-dichloro-benzoic acid(commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene washeated to reflux until no more gas evolution was observed. After coolingto rt the mixture was concentrated. The concentrate was diluted withdichloroethane and added to AlCl₃ (7.0 g, ˜53 mmol) in dichloroethane at10–20° C. Ethylene was bubbled through the mixture for 4 h. The mixturewas stirred overnight and quenched with 4 N HCl. The resulting layerswere separated and the aqueous layer was extracted with Et₂O (3×250 mL).The combined organic extracts were washed with H₂O (3×150 mL), saturatedNaHCO₃ (3×150 mL), brine (1×150 mL), dried over MgSO₄ and concentrated.The concentrate was added to a slurry of AlCl₃ (9.0 g) and NaCl (2.4 g)at 130° C. The resulting mixture was stirred at 180° C. for 2 hoursafter which it was cooled to room temperature and quenched with icefollowed by concentrated HCl. The mixture was extracted with CH₂Cl₂(3×500 mL) and the combined organic extracts were concentrated andpurified by column chromatography using 20% EtOAc:hexane eluant to give6.8 g (80%) of 6,7-dichloro-1-indanone. Use of 6,7-dichloro-indan-1-onein Method NINETEEN produced4-(4,5-dichloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound153).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.31 (d, J=7.8 Hz, 11H), 7.14 (d, J=8.1 Hz,1H), 6.62 (s, 1H), 3.67–3.56 (m, 1H), 3.42–3.31 (m, 2H), 3.09–2.99 (m,2H).

EXAMPLE NINETEEN-6 (COMPOUND 154)

Use of 3-methyl-indan-1-one (commercially available from Aldrich) inMethod NINETEEN produced4-(1-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 154).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.20–7.10 (m,4H), 6.69 (s, 1H), 3.17–3.04 (m, 2H), 2.96–2.78 (m, 2H), 1.22 (d, J=6.6Hz, 3H).

EXAMPLE NINETEEN-7 (COMPOUND 155)

Use of 7-iodo-indan-1-one (Intermediate SIXTEENbeta3) in Method NINETEENproduced 4-(4-iodo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound155).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.55 (d, J=8.1Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.8 Hz, 1H), 6.63 (s, 1H),3.48–3.39 (m, 2H), 3.18–3.03 (m, 2H), 2.92–2.83 (m, 1H).

EXAMPLE TWENTY (COMPOUND 156) Procedure for the Preparation4-(4,5-difluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 156)

A solution of 2,3-difluorocinnamic acid (2.8 g, 15.2 mol) (commerciallyavailable from Lancaster) (Intermediate TWENTY-1) in ethanol (100 mL)was hydrogenated with H₂ (balloon) and 10% Pd/C (0.3 g) at rt for 16 h.The mixture was filtered through Celite® and the solvent was evaporatedto give 3-(2,3-difluoro-phenyl)-propionic acid as a solid, 2.68 g (98%).A mixture of 3-(2,3-difluoro-phenyl)-propionic acid (2.7 g, 14.4 mmol)in CH₂Cl₂ at 0° C. was treated with oxalyl chloride (8.7 mL, 2 M inCH₂Cl₂) and a few drops of DMF. The reaction mixture was stirred for 2 hat rt. The solution was decanted from the dark colored residues and thesolvent was removed under vacuum. The residue was dissolved in CH₂Cl₂(20 mL) and added to a mixture of AlCl₃ (1.92 g, 14.4 mmol) in CH₂Cl₂(25 mL). The mixture was heated at 50° C. for 16 h. The entire mixturewas poured into ice water. The aqueous phase was removed and extractedwith CH₂Cl₂. The organic layers were combined, washed with sat. NaHCO₃solution, brine, and dried over Na₂SO₄, filtered, and evaporated todryness. The residue was purified by chromatography on silica gel with20% EtOAc:hexane to give 4,5-difluoro-indan-1-one (IntermediateTWENTY-2), 1.65 g (68%).

A solution of give 4,5-difluoro-indan-1-one (Intermediate TWENTY-2)(1.36 g, 8.10 mmol) in benzene (20 mL) and ether (20 mL) was treatedwith a few iodine crystals followed by ethyl bromoacetate (1.4 mL, 12.3mmol) and zinc dust (1.60 g, 24.4 mmol). The mixture was heated to 70°C. for 16 h at rt. The mixture was cooled to rt and filtered through apad of Celite. The filtrate was evaporated and the residue((4,5-difluoro-1-hydroxy-indan-1-yl)-acetic acid ethyl ester) wasdissolved in benzene and treated with a catalytic amount of pTsOH. Themixture was heated at reflux in a Dean-Stark trap for 16 h. The mixturewas cooled to rt and diluted with aqueous acid and ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The organic layers werepooled and dried over MgSO₄. The solution was filtered, evaporated andpurified by chromatography on silica gel with 10 to 15% ether:hexane togive a mixture of E- and Z-(4,5-difluoro-indan-1-ylidene)-acetic acidethyl ester (Intermediate TWENTY-3) as a solid, 1.1 g.

A mixture of E- and Z-(4,5-difluoro-indan-1-ylidene)-acetic acid ethylester (Intermediate TWENTY-3) (1.1 g) in EtOAc (25 mL) was hydrogenatedwith 10% Pd/C (0.16 g) under H₂ (balloon) at rt for 16 h. The mixturewas filtered through a bed of Celite® and the filtrate was evaporatedunder vacuum. The ester, (4,5-difluoro-indan-1-yl)-acetic acid ethylester (1.1 g, 4.58 mmol) in THF (60 mL) and MeOH (1 mL) was treated withLiBH₄ (0.21 g, 8.5 mmol) at 65° C. for 5 h. The mixture was cooled andTHF was removed under vacuum. The solution was diluted with EtOAc andsat. NH₄Cl. The layers were separated and the organic layer was driedover MgSO₄ and filtered. After evaporation, the alcohol,2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) was isolatedas a clear, colorless oil, 1.7 g, (88%). Use,2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) in MethodSEVENTEEN produced4-(4,5-difluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound156).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.05–6.96 (m, 1H), 6.89–6.85 (m, 1H), 6.52(s, 1H), 3.46–3.38 (m, 1H), 3.00–2.83 (m, 3H), 2.61–2.54 (dd, J=9.0, 6.0Hz, 1H), 2.36–2.24 (m, 1H), 1.90–1.79 (m, 1H).

EXAMPLE TWENTY-1 (COMPOUND 157)

Use of 6-fluoro-indan-1-one (commercially available from Lancaster) inMethod TWENTY produced4-(6-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound157).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.18–7.13 (m, 1H), 6.87–6.82 (m, 2H), 6.52(m, 1H), 3.45–3.34 (m, 1H), 2.92–2.74 (m, 3H), 2.60–2.52 (dd, J=9.0, 6.0Hz, 1H), 2.31–2.19 (m, 1H), 1.84–1.73 (m, 1H).

EXAMPLE TWENTY-2 (COMPOUND 158)

Use of 3-(3,4-difluoro-phenyl)-acrylic acid (commercially available fromAldrich) in Method TWENTY produced4-(5,6-difluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 158).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.10–7.00 (m, 2H), 6.53 (s, 1H), 3.41–3.36 9m, 1H), 2.90–2.79 (m, 3H), 2.60–2.52 (dd, J=9.6, 5.7 Hz, 1H), 2.32–2.20(m, 1H), 1.86–1.74 (m, 1H).

EXAMPLE TWENTY-3 (COMPOUND 159)

Use of 2-fluorocinnamic acid (commercially available from Aldrich) inMethod TWENTY produced4-(4-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound159).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.18–7.11 (m, 1H), 6.94 (d, J=7.3 Hz, 1H),6.85 (t, J=8.4 Hz, 1H), 6.50 (s, 1H), 3.50–3.42 (m, 1H), 2.93–2.80 (m,3H), 2.62–2.54 (m, 1H), 2.30–2.24 (m, 1H), 1.86–1.80 (m, 1H).

EXAMPLE TWENTY-4 (COMPOUND 160)

Use of 2,5-dimethylcinnamic acid (commercially available from Lancaster)in Method TWENTY produced 4,7-dimethylindan-1-one. Use of4,7-dimethylindan-1-one in Method A produced4-(4,7-dimethyl-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 160).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.6 (s, 1H), 6.86–6.80 (m,2H), s, 1H), 3.43–3.36 (m, 1H), 2.83–2.47 (m, 3H), 2.23–2.18 (m, 3H),2.12 (s, 3H), 1.95–1.76 (m, 2H).

EXAMPLE TWENTY-5 (COMPOUND 161)

Use of 8-chloro-3,4-dihydro-2H-naphthalen-1-one (Intermediate SIXTEEN-1)in Method TWENTY (note.: for both of the hydrogenation procedures:substitute 5% Rh on Alumina at 50 psi H₂ for any Pd/C catalyst) produced4-(8-chloro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 161).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (m, 1H), 7.22 (d, J=7.2Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 6.63 (s, 1H), 2.81–2.60 (m, 3H),2.49–2.35 (m, 2H), 1.80–1.50 (m, 4H).

EXAMPLE TWENTYTWO (COMPOUND 162) Procedure for the Synthesis of4-(5,6,7,8-tetrahydro-quinolin-6-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 162)

Use of 7,8-dihydro-6H-quinolin-5-one (Intermediate TWENTYTWO-1)(obtained as described in Molina, et. al. Tetrahedron 1995, 51, 1265,incorporated herein by reference) in Method E produced6-(1H-imidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (IntermediateTWENTYTWO-2). To a solution of6-(1H-imidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (IntermediateTWENTYTWO-2) (1.31 g, 227 mmol) in diethylene glycol (10 mL) was addedhydrazine (6.3 mL, 200 mmol) followed by KOH (4.85 g, 56.2 mmol). Themixture was heated to 170° C. for 5 h. The mixture was diluted withwater (200 mL) and sat. NaHCO₃. The aqueous solution was extracted withCHCl₃ (3×50 mL). The combined organic portions were washed with waterand brine. The organic layer was dried over MgSO₄, filtered andevaporated to give6-(1H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline as a foamysolid, 1.15 g (92%). By the applicable process steps described in MethodA, the imidazole compound was used to produce4-(5,6,7,8-tetrahydro-quinolin-6-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 162).

¹H NMR (300 MHz, DMSO-d⁶) δ 11.9 (s, 1H), 11.7 (s, 1H), 8.29 (d, J=3.3Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.10 (dd, J=7.5, 4.5 Hz, 1H), 6.62 (s,1H), 2.93–2.71 (m, 3H), 2.51–2.37 (m, 3H), 2.04–1.90 (m, 2H), 1.50–1.37(m, 1H).

EXAMPLE TWENTYTHREE (COMPOUND 163) Procedure for the Synthesis of4-(4-chloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 163)

Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1) (commerciallyavailable from Aldrich) in the applicable process steps described inMethod TWENTY and Method NINETEEN produced 4-chloro-indan-2-carboxylicacid methyl ester (Intermediate TWENTYTHREE-2). Use of4-chloro-indan-2-carboxylic acid methyl ester (IntermediateTWENTYTHREE-2) in the applicable process steps described in MethodSEVENTEEN and Method A produced4-(4-chloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 163).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.13 (brs, 3H), 6.60 (s, 1H), 3.61–3.50 (m,1H), 3.38–3.28 (m, 2H), 3.09–2.93 (m, 2H).

EXAMPLE TWENTYTHREE-1 (COMPOUND 164)

Use of 3,5-difluorocinnamic acid (commercially available from Aldrich)in Method TWENTY produced 5,7-difluoro indan-1-one. Use of 5,7-difluoroindan-1-one in Method TWENTYTHREE produced4-(4,6-difluoro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound164).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.1 (s, 1H), 11.7 (s, 1H), 7.01–6.96 (m,2H), 6.66 (s, 1H), 3.57–3.46 (m, 1H), 3.26–3.16 (m, 2H), 3.01–2.83 (m,2H).

EXAMPLE TWENTYTHREE-2 (COMPOUND 165)

Use of 3-fluoro-5-methoxycinnamic acid (commercially available fromAldrich) in the applicable process steps described in Method TWENTY andMethod NINETEEN produced 4-fluoro-6-methoxy-indan-2-carboxylic acidmethyl ester as an intermediate. This material was subjected to theapplicable process steps described in Method SEVENTEEN and Method A inorder to produce4-(4-fluoro-6-methoxy-indan-2-yl)-1,3-dihydro-imidazole-2-thione(Compound 165).

¹H NMR (500 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 6.68–6.65 (m,2H), 6.62 (s, 1H), 3.45–3.38 (m, 1H), 3.17–3.12 (m, 1H), 3.10–3.04 (m,1H), 2.91–2.86 (m, 1H), 2.73–2.69 (m, 1H).

EXAMPLE TWENTYFOUR (COMPOUND 166) Procedure for the Synthesis of4-(4-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound166)

Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1) (commerciallyavailable from Aldrich) in the applicable process steps described inMethod TWENTY produced 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1).Triethylphosphonoacetate (3.5 mL, 17.2 mmol) was added to a mixture ofNaH (0.69 g, 12.2 mmol) in THF (25 mL). After 30 m, a solution of4-chloro-indan-1-one (Intermediate TWENTYFOUR-1) (1.46 g, 8.8 mmol) inTHF (20 mL) was added to the mixture. The reaction mixture was allowedto stir for 16 h at rt. The solution was quenched with water and dilutedwith EtOAc. The layers were separated and the organic phase was driedover MgSO₄, filtered and evaporated under reduced pressure. The residuewas subjected to chromatography on silica gel with 3% EtOAc:hexane. Thefractions that contained the unsaturated esters were collected andevaporated to give the product, 1.67 g. The mixture of esters (1.67 g,7.06 mmol) in EtOAc was hydrogenated in the presence of 5% Rh on Alumina(0.14 g) at 40–50 psi H₂ at rt for 2 d. The mixture was filtered througha plug of Celite® and concentrated in vacuo to produce(4-chloro-indan-1-yl)-acetic acid ethyl ester (IntermediateTWENTYFOUR-2). Use of (4-chloro-indan-1-yl)-acetic acid ethyl ester(Intermediate TWENTYFOUR-2) in the applicable process steps described inMethod SEVENTEEN and Method A produced4-(4-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound166).

¹H NMR (300 MHz, MeOH-d⁴) δ 7.16–7.04 (m, 3H), 6.51 (s, 1H), 3.53–3.44(m, 1H), 3.01–2.80 (m, 3H), 2.60 (dd, J=8.7, 6 Hz, 1H), 2.31–2.19 (m,1H), 1.85–1.74 (m, 1H).

EXAMPLE TWENTYFOUR-1 (COMPOUND 167)

Use of 4-bromoindanone (obtained by the procedures in Example NINETEEN-1(Compound 149) in Method TWENTYFOUR produced4-(4-bromo-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound167).

¹H NMR (300 MHz, MeOH-d⁴) § 7.31 (dd, J=7.5, 0.6 Hz, 1H), 7.11–7.02 (m,2H), 6.51 (s, 1H), 3.56–3.47 (m, 1H), 2.99–2.78 (m, 3H), 2.63–2.55 (m,1H), 2.30–2.19 (m, 1H), 1.84–1.73 (m, 1H).

EXAMPLE TWENTYFOUR-2 (COMPOUND 168)

Use of 6,7-dihydro-5H-quinolin-8-one (obtained as described in Lemke,et. al. J. Med. Chem., 1977, 20, 1351, incorporated herein by reference)in the applicable process steps described in Method TWENTYFOUR producedE- and Z-(6,7-dihydro-5H-quinolin-8-ylidene)-acetic acid ethyl ester.Note: The reduction procedure for the mixture of esters was as follows.E- and Z-(6,7-dihydro-5H-quinolin-8-ylidene)-acetic acid ethyl ester(2.3 g, 10.6 mmol) was hydrogenated in a mixture of TFA (20 mL), andPtO₂ (150 mg) under 50 psi H₂ for 50 m at rt. The mixture was filteredthrough a bed of Celite® and using EtOAc. The filtrate was added tocrushed ice and made basic (pH 8) with NaOH solution. The aqueous layerwas extracted with EtOAc and the pooled organic layers were dried overMgSO₄, filtered, added to silica gel and evaporated to dryness. Thematerial was eluted through a column of silica gel with 20% EtOAc:hexaneto give (5,6,7,8-tetrahydro-quinolin-8-yl)-acetic acid ethyl ester 1.77g (77%). Use of (5,6,7,8-tetrahydro-quinolin-8-yl)-acetic acid ethylester in the applicable process steps described in Method SEVENTEEN andMethod A produced4-(5,6,7,8-tetrahydro-quinolin-8-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 168).

¹H NMR (300 MHz, MeOH-d⁴) δ 8.36 (d, J=5.1 Hz, 1H), 7.53 (d, J=7.5 Hz,1H), 7.18 (dd, J=4.5, 7.5 Hz, 1H), 6.54 (s, 1H), 3.10–3.00 (m, 2H), 2.78(brs, 2H), 2.73–2.64 9 m, 1H), 1.90–1,82 (m, 2H), 1.75–1.68 (m, 2H).

EXAMPLE TWENTYFIVE (COMPOUND 169) Procedure for the Synthesis of[2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(Compound 169)

A solution of 2-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E4) (2.11 g, 9.3 mmol) in DMF (25 mL) was treated withtriethyl amine (1.9 mL, 13.6 mmol) and triphenylmethylchloride(tritylchloride) (2.74 g, 9.6 mmol, added dropwise in DMF (25 mL)).After 16 h at rt the mixture was partitioned between water anddichloromethane. The aqueous layer was extracted with dichloromethaneand the organic layers were collected and dried over MgSO₄, filtered andconcentrated onto silica gel. The material was placed on a column ofsilica gel and eluted with 50% EtOAc:hexane. The appropriate fractionswere collected and2-(1-trityl-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate TWENTYFIVE-1) was isolated as a white solid, 3.58 g (82%).Sodium hydride (1.2 eqv) in DMF (25 mL) was reacted withdiethyl(cyanomethyl)phosphonate (available from Aldrich) (1.3 eqv)(added dropwise). After 30 m at rt a solution of2-(1-trityl-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate TWENTYFIVE-1) in DMF (20 mL) was added in a dropwisefashion to the mixture. The mixture was stirred for 16 h at rt. Anotheraliquot (1.2 eqv) of prepared NaH and diethyl(cyanomethyl)phosphonate inDMF was added to the mixture and the solution was heated to 40° C. for18 h. The mixture was quenched with sat. NH₄Cl, diluted with water, andextracted with EtOAc. The organic layers were dried over MgSO₄, filteredand concentrated onto silica gel. The material was eluted from a columnof silica gel with 40% EtOAc:hexane. Two isomers E and Z (trans and cis)were collected from the column and carried onto the next step. Asolution of the mixed trans and cis isomers of[2-(1-trityl-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(0.33 g) was stirred in 95% TFA (trifluoroacetic acid, 9.5 mL) and water(0.5 mL) for 2 h at rt to remove the trityl protective group. The pH ofthe mixture was adjusted with 2M NaOH and extracted with EtOAc. Themixture was subjected to an aqueous work-up and concentrated onto silicagel. The material was eluted from a column of silica gel with 5%NH₃.MeOH in CH₂Cl₂ to give[2-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(trans isomer) (Intermediate TWENTYFIVE-2) as a clear colorless oil(˜0.1 g). The cis isomer (Intermediate TWENTYFIVE-3) was isolated fromthe same process (0.27 g). Use of[2-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(Intermediate TWENTYFIVE-2) in the applicable process steps described inMethod A produced[2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(Compound 169 trans isomer)

H NMR (300 MHz, MeOH-d⁴) δ 8.04 (d, J=8.0 Hz, 1H), 7.40 (t, J=7.5 Hz,1H), 7.30–7.26 (m, 2H), 6.53 (s, 1H), 5.46 (s, 1H), 3.03–2.96 (m, 2H),2.89–2.83 (m, 1H), 2.61 (d, J=7.0 Hz, 2H), 2.12–2.06 (m, 1H), 1.86–1.80(m, 1H).

EXAMPLE TWENTYFIVE-1 (COMPOUND 170)

Use of Intermediate TWENTYFIVE-3 (see above preparation) in theapplicable process steps described in Method A produced[2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-acetonitrile(Compound 170 cis isomer).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.0 (s, 1H), 11.7 (s, 1H), 7.71 (d, J=8.1Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.25–7.20 (m, 2H), 6.52 (s, 1H), 6.17(s, 1H), 3.44–3.36 (m, 1H), 3.02–2.91 (m, 1H), 2.76–2.70 (m, 1H),2.58–2.38 (m, 2H), 1.87–1.84 (m, 2H).

EXAMPLE TWENTYSIX (COMPOUND 171) Procedure for the Synthesis of4-(5-methyl-3,6-dihydro-2H-pyran-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 171)

A solution of 3-(t-butyl-dimethyl-silanyloxy)-propionaldehyde(Intermediate TWENTYSIX-1) (1.5 g, 7.96 mmol) (obtained as described inBerque, et al J. Org. Chem. 1999, 373, incorporated herein by reference)in diethyl ether (60 ml), at −30° C., was treated with a solution ofallylMgBr (9.6 mL, 1.0 M in ether). The mixture was allowed to warm to0° C. and remained at this temperature for 1 h. The solution was dilutedwith water (30 mL) and the layers were separated. The aqueous layer wasextracted with ether (2×15 mL). The organic phases were combined anddried over MgSO₄. The solution was filtered and evaporated under reducedpressure. The crude material was purified by chromatography on SiO₂ with10% EtOAc:hexane to give 1-(t-butyl-dimethyl-silanyloxy)-hex-5-en-3-ol(Intermediate TWENTYSIX-2) 1.7 g (93%).1-(t-Butyl-dimethyl-silanyloxy)-hex-5-en-3-ol (Intermediate TWENTYSIX-2)(0.94 g, 4.1 mmol) in THF (10 mL) was treated with KHMDS (14.8 mL, 0.5 Min toluene) at 0° C. to 20° C. for 1 h. 2-Bromo-2-methyl propene (1.1 gmL, 8.2 mmol) was added via syringe at 0° C. The mixture was allowed towarm to rt. Stirring was continued for 16 h. The mixture was quenchedwith water. The organic layer was dried over MgSO₄, filtered andevaporated in vacuo. The residue was purified by chromatography on SiO₂with 5% ether:hexane to givet-butyl-dimethyl-[3-(2-methyl-allyloxy)-hex-5-enyloxy]-silane(Intermediate TWENTYSIX-3) 1.16 g, (86%). A solution oft-butyl-dimethyl-[3-(2-methyl-allyloxy)-hex-5-enyloxy]-silane(Intermediate TWENTYSIX-3) (1.0 g, 3.73 mmol) in CH₂Cl₂ was treated withGrubbs catalyst (260 mg, 0.32 mmol) (commercially available from Strem).The progress of the reaction was followed by TLC and was complete after3 d at rt. The solvent was removed under vacuum and the material waspurified by chromatography on silica gel with 2% ether hexane to givet-butyl-dimethyl-[2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethoxy]-silane(Intermediate TWENTYSIX-4), ˜450 mg. A solution oft-butyl-dimethyl-[2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethoxy]-silane(Intermediate TWENTYSIX-4) (˜450 mg) in ether (7 mL) was treated withTBAF (5 mL, 1 M in THF) at rt for 3 h. The mixture was diluted withether (20 mL) and washed with water (1×10 mL). The organic layer wasisolated and dried over MgSO₄, filtered and evaporated under vacuum.Chromatography on SiO₂ with 30 to 60% EtOAc:hexane gave2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethanol, 100 mg. A solution ofoxalyl chloride (0.5 mL, 1 mmol) in CH₂Cl₂ (1 mL) was treated with DMSO(0.080 mL, 1.1 mmol) at −78° C. for 30 m. A solution of2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethanol (100 mg) was added andthe mixture was allowed to stir for 30 nm. Triethylamine (0.5 mL, ˜3mmol) was added and the mixture was allowed to stir for 45 m. Thesolution was quenched with water and CH₂Cl₂ (10 mL). The organic layerwas isolated, dried and evaporated. The residue was purified on silicagel with 30% EtOAc:hexane to give(5-methyl-3,6-dihydro-2H-pyran-2-yl)-acetaldehyde (IntermediateTWENTYSIX-5), 90 mg. Use of(5-methyl-3,6-dihydro-2H-pyran-2-yl)-acetaldehyde (IntermediateTWENTYSIX-5) in the applicable process steps described in Method Aproduced4-(5-methyl-3,6-dihydro-2H-pyran-2-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 171).

¹H NMR (300 MHz, CDCl₃) δ 10.8 (s, 1H), 9.95 (s, 1H), 6.47 (s, 1H), 5.46(s, 1H), 4.05 (s, 2H), 3.73–3.62 (m, 1H), 2.76–2.63 (m, 1H), 2.58 (dd,J=8.4, 7.5 Hz, 1H), 2.03–1.88 (m, 2H), 1.61 (s, 3H).

EXAMPLE P (COMPOUND 41) Method P: Procedure for the Preparation4-(12,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 41)

A solution of4-(1,2,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1H-imidazole; fumaratesalt (Intermediate A5 as described in Example A, 340 mg, 1.81 mmol) inTHF (15 mL) and water (15 mL) was treated with NaHCO₃ (1.52 g, 18 mmol)at rt for 30 m. Phenyl chloroformate (600 mL, 4.7 mmol) was added andstirring was continued for 1 h at 65° C. The mixture was diluted withwater (30 mL) and extracted with EtOAc (3×30 mL). The organic portionswere combined and freed of solvent. The residue was dissolved in EtOH(15 mL): water (15 mL) and treated with Na₂CO₃ (500 mg) for 1.5 h at 95°C. The mixture was cooled to rt and the product was collected on a glassfrit to give a white solid (˜50%)4-(1,2,3,4,5,6-Hexahydro-pentalen-1-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 41).

¹H NMR (300 MHz, DMSO-d⁶): δ 9.69 (s, 1H), 9.38 (s, 1H), 5.92 (s, 1H),2.70 (brs, 1H), 2.40–2.30 (m, 3H), 2.12–1.99 (m, 9H), 1.85–1.78 (m, 1H).

EXAMPLE P2 (COMPOUND 42)

Use of 3-methyl-cyclopent-2-enone (commercially available from Aldrich)in the applicable steps combined from Method A and Method P produced4-(3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound42).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 9.67 (s, 1H), 9.38 (s, 1H), 5.93 (s,1H), 5.25 (s, 1H), 3.16 (d, J=5.4 Hz, 1H), 2.82–2.11 (m, 3H), 2.0–1.96(m, 1H), 1.67 (s, 3H), 1.50–1.46 (m, 1H).

EXAMPLE P3 (COMPOUND 43)

Use of 2-ethyl-cyclopent-2-enone (commercially available from Aldrich)in the applicable steps combined from Method A and Method P produced4-(2-ethyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound43).

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.05 (s, 1H), 5.38 (brs, 1H), 3.31–3.29(m, 1H), 2.75 (brs, 1H), 2.67–2.60 (m, 1H), 2.25–1.98 (series of m, 7H),1.62–1.55 (m, 1H), 1.07 (t, J=10 Hz, 3H).

EXAMPLE P4 (COMPOUND 44)

Use of 2,3-dimethyl-cyclopent-2-enone (commercially available fromAldrich) in the applicable steps combined from Method A and Method Pproduced4-(2,3-dimethyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 44).

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.04 (s, 1H), 2.73 (brs, 1H), 2.68–2.61(m, 1H), 2.27–2.19 (m, 2H), 2.13–2.05 (m, 1H), 1.99–1.87 (m, 1H), 1.63(s, 6H), 1.55–1.46 (m, 1H).

EXAMPLE P5 (COMPOUND 45)

Use of 3,4-dihydro-2H-naphthalen-1-one (commercially available fromAldrich) in the applicable steps combined from Method A and Method Pproduced4-(1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 45).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 9.86 (s, 1H), 9.40 (s, 1H), 7.16–7.04(m, 4H), 5.96 (s, 1H), 2.97 (brs, 1H), 2.69–2.29 (series of m, 5H),1.66–1.60 (m, 3H).

EXAMPLE P6 (COMPOUND 46)

Use of indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-indan-1-ylmethyl-1,3-dihydro-imidazol-2-one (Compound 46).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 9.83 (s, 1H), 9.43 (s, 1H), 7.21–7.13(m, 4H), 5.95 (s, 1H), 3.40–3.28 (m, 1H), 2.95–2.63 (m, 3H), 2.30–2.12(m, 214), 1.70–1.59 (m, 1H).

EXAMPLE P7 (COMPOUND 47)

Use of 3-methyl-indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-(3-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 47).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ (diastereomers) 9.85 (s, 1H), 9.45(s, 1H), 7.17–7.08 (m, 4H), 6.00 (5.92) (s, 1H), 3.34–2.86 (series of m,2H), 2.37–2.22 (series of m, 2H), 1.99–1.95 (m, 1H), 1.71–1.67 (m, 1H),1.18 (1.25) (d, J=6.5 Hz, 3H), 1.50–1.14 (m, 2H).

EXAMPLE P8 (COMPOUND 48)

Use of 4-methyl-indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-(4-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one.

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 9.83 (s, 1H), 9.44 (s, 1H), 7.02–6.91(m, 3H), 5.92 (s, 1H), 3.28 (brs, 1H), 2.79–2.74 (m, 1H), 2.66–2.63 (m,2H), 2.25–2.10 (m, 2H), 2.17 (s, 3H), 1.65–1.61 (m, 1H).

EXAMPLE P9 (COMPOUND 49)

Use of 5-fluoro-indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-(5-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 49).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 9.83 (s, 1H), 9.44 (s, 1H), 7.14–6.91(m, 3H), 5.95 (s, 1H), 3.31–3.28 (m, 1H), 2.88–2.60 (m, 3H), 2.31–2.14(m, 2H), 1.75–1.70 (m, 1H).

EXAMPLE P10 (COMPOUND 50)

Use of 5-methoxy-indan-1-one (commercially available from Aldrich) inthe applicable steps combined from Method A and Method P produced4-(5-methoxy-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 50).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 9.81 (s, 1H), 9.43 (s, 1H), 7.02–6.67(m, 3H), 5.94 (s, 1H), 3.26–3.23 (m, 1H), 3.70 (s, 3H), 2.83–2.59(series of m, 3H), 2.26–2.10 (m, 2H), 1.67–1.63 (m, 1H).

EXAMPLE P11 (COMPOUND 51)

Use of 5-bromo-indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-(5-bromo-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 51).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 9.83 (s, 1H), 9.45 (s, 1H), 7.39 (d,J=5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.95 (s,1H), 3.29 (brs, 1H), 2.87–2.61 (series of m, 3H), 2.31–2.14 (m, 2H),1.70–1.68 (m, 1H).

EXAMPLE P12 (COMPOUND 52)

Use of 6-methyl-indan-1-one (commercially available from Aldrich) in theapplicable steps combined from Method A and Method P produced4-(6-methyl-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 52).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 9.87 (s, 1H), 9.48 (s, 1H), 7.07 (d,J=7.5 Hz, 1H), 6.97–6.93 (m, 2H), 5.96 (s, 1H), 3.29–3.26 (m, 1H),3.80–2.66 (m, 3H), 2.25 (s, 3H), 2.36–2.11 (m, 2H), 1.66–1.62 (m, 1H).

EXAMPLE P13 (COMPOUND 53)

Use of 6-methoxy-indan-1-one (commercially available from Aldrich) inthe applicable steps combined from Method A and Method P produced4-(6-methoxy-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 53).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 9.86 (s, 1H), 9.48 (s, 1H), 7.08 (d,J=7.5 Hz, 1H), 6.69 (brs, 2H), 3.69 (s, 3H), 3.30–3.27 (m, 1H),2.78–2.65 (series of m, 3H), 2.29–2.10 (m, 2H), 1.68–1.64 (m, 1H).

EXAMPLE Q (COMPOUND 54) Procedure for Preparation of4-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 54) and4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 55)

2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E4, as described in Example E, 1.4 g) was subjected to theapplicable steps of Method P to provide4-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 54) isolated as a white solid (˜50%).

¹H NMR (300 MHz, DMSO-d₆ w/TMS) δ 9.70 (s, 1H), 9.45 (s, 1H), 7.88–7.86(m, 1H), 7.57–7.51 (m, 1H), 7.37–7.32 (m, 2H), 2.95–2.90 (m, 3H),2.82–2.70 (m, 1H), 2.30–2.20 (m, 1H), 2.15–2.05 (m, 1H), 1.75–1.68 (m,1H).

Synthesis of4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 55) from 6,7-dihydro-5H-benzo[b]thiophen-4-one wasaccomplished from4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1H-imidazole(Intermediate F3 as described in Example A) in the applicable reactionsequence of Method P, and shown below.

4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-1,3-dihydro-imidazol-2-one(Compound 55):

¹H NMR (300 MHz, DMSO-d⁶) δ 9.72 (s, 1H), 9.42 (s, 1H), 7.21 (d, J=6.0Hz, 1H), 6.75 (d, J=6.0 Hz, 1H), 5.99 (s, 1H), 2.83–2.60 (m, 3H),2.28–2.15 (m, 3H), 2.02–1.85 (m, 2H), 1.43–1.35 (m, 1H).

EXAMPLE R (COMPOUND 56) Method R: Synthesis of4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 56)

8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate R1, 1.02g, 3.70 mmol) (obtainable as described in the publication by Ciufoliniet. al. J. Amer. Chem. Soc. 1991, 113, 8016, incorporated herein byreference) was dissolved in acetone (100 mL): H₂O (5 mL) and reactedwith TsOH (140 mg, 0.74 mmol) at 45° C. for 5 h. After a standardaqueous work-up the material was purified by chromatography on SiO₂ togive 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless oil (97%).

A solution of LDA (33 ml, 1.5 M in Et₂O) in THF (50 mL) at −78° C. wastreated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). Themixture was warmed to 0° C. over 30 m before re-cooling to −78° C. andadding HMPA (7 mL). Methyl cyanoformate (4.1 mL, 85 mmol) was added andthe mixture was stirred for 15 m before aqueous quench and work-up. Theproduct was purified by chromatography on SiO₂ with 10% EtOAc:Hx.5-(2-Benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester wasisolated, 5.8 g (49%) and reduced with an equivalent of NaBH₄ in MeOH at−10° C. to provide the alcohol (Intermediate R2). Intermediate R2 waspurified by chromatography on SiO₂ with 30 to 50% EtOAC:Hx. (˜90%yield).

A solution of 5-(2-benzyloxy-ethyl)-2-hydroxy-cyclohexanecarboxylic acidmethyl ester (Intermediate R2, 0.72 g, 2.48 mmol) in pyridine (10 mL)was treated with SOCl₂ (0.73 mL, 12.4 mmol) at −20° C. The mixture wasallowed to react for 15 m and was then warmed to 55° C. for 16 h. Thesolvents were removed under vacuum and the residue was diluted in etherat 0° C. The solution was quenched with water, washed with 1M HCl, 5%NaOH and brine. The organic material was dried over MgSO₄ filtered andfreed of solvent. The mixture was diluted with benzene and water wasremoved by azeotropic distillation under vacuum. The residue wasdissolved in benzene (15 mL) and DBU (0.76 mL, 5 mmol) was added. Themixture was reacted for 30 m at rt. After work-up and chromatography onSiO₂ with 20% EtOAc:Hx 5-(2-benzyloxy-ethyl)-cyclohex-1-enecarboxylicacid methyl ester (Intermediate R3) was isolated 0.56 g (82%).

Intermediate R3 was dissolved in THF (100 mL) and added to a solution ofDIBAL (70 mL, 1M in hexanes) in THF (160 mL) at −35° C. for 35 m. Themixture was quenched with Rochelle's salt solution, and extracted withether. The dried residue was purified by chromatography on SiO₂ with 30%EtOAc:Hx to yield [5-(2-benzyloxy-ethyl)-cyclohex-1-enyl]-methanol 4.6 g(80%). A solution of the alcohol (4.0 g, 18.7 mmol) in DMF (60 mL) wastreated with triethylamine (3 mL) followed by TBSCl (3.0 g, 22.4 mol)for 20 m at rt. The residue was isolated from an aqueous work-up andpurified by chromatography to give[5-(2-benzyloxy-ethyl)-cyclohex-1-enylmethoxy]-tert-butyl-dimethyl-silane(Intermediate R4, 3.6 g (63%). The benzyl and tert-butyl-dimethyl-silylprotected alcohol (Intermediate R4, 2.0 g, 5.55 mmol) in THF (20 mL) wascooled to −70° C. and NH₃ was condensed in this flask (20 mL). Na chunkswere added and the mixture was allowed to stir at −70° C. for 15 m. Themixture was warmed to −30° C. for 20 m. The mixture was quenched withNH₄Cl and the alcohol from which the benzyl protecting group has beenremoved was isolated by extraction. The residue was purified bychromatography on SiO₂ with 25% EtOAc:Hx (99%).

The alcohol was oxidized by the standard “Swern” protocol (see MancusoSynthesis supra) as follows. The alcohol2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-ethanol(1.3 g, 5.89 mmol) was added to a solution of oxalyl chloride (3.55 mL,7.1 mmol) in CH₂Cl₂ (30 mL) with DMSO (0.63 mL, 8.9 mmol) at −78° C.After 40 m, NEt₃ (2.51 mL) was added and the mixture was warmed to rt.After standard aqueous work-up and purification,[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-acetaldehyde(Intermediate R5) was isolated (˜95%). The aldehyde (Intermediate R5)was subjected to the applicable steps of Method P to form4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 56).

¹H NMR (300 MHz, CD₃OD-d⁴) δ 6.04 (s, 1H), 5.66 (s, 1H), 3.90 (s, 2H),2.34 (d, J=7.2 Hz, 2H), 2.15–2.06 (m, 3H), 1.85–1.65 (m, 3H), 1.29–1.15(m, 1H).

EXAMPLE R2 (COMPOUND 57) Procedure for the Synthesis of4-(3-Methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound57)

5-(2-Benzyloxy-ethyl)-cyclohex-1-enecarboxylic acid methyl ester(Intermediate R3 obtained above in Example R1 in accordance with MethodR) was reduced with DIBAL. The resulting alcohol (Intermediate R7, 1.18g, 4.81 mmol) in THF (20 mL) at 0° C. was treated with sulfurtrioxide-pyridine. (1.15 g, 7.21 mmol) for 3 h. LiAlH₄ (15 mL, 15 mmol)was injected into the mixture at 0° C. The solution was allowed to warmto rt for 18 h. The mixture was subjected to an aqueous work-up andpurified by chromatography to give[2-(3-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate R8,0.90 g, 82%). Deprotection with Na/NH₃ and subsequent “Swern” oxidationproduced (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9).(3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9) was subjectedto the applicable steps combined from Method A and Method P to yield4-(3-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound57).

¹H NMR (300 MHz, DMSO-d⁶) d 9.64 (s, 1H), 9.35 (s, 1H), 5.92 (s, 1H),2.14 (d, J=6.9 Hz, 2H), 1.94–1.74 (m, 4H), 1.62–1.50 (m, 2H), 1.57 (s,3H), 1.09–0.96 (m, 1H).

EXAMPLE R3 (COMPOUND 58) Synthesis of4-(3-ethyl-4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 58)

(3-Ethyl-4-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate K1 asprepared in Example K) was subjected to the applicable steps combinedfrom Method A and Method P to yield4-(3-ethyl-4-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 58).

¹H NMR (300 MHz, CD₃OD) δ 6.05 (s, 1H), 2.29 (d, J=6.9 Hz, 2H),2.00–1.97 (m, 4H), 1.75–1.59 (m, 6H), 1.26–1.12 (m, 1H), 1.0–0.88 (m,4H).

EXAMPLE R4 (COMPOUND 59) Procedure for the Preparation of4-(3-ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound59)

A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate R10, 6.8g, 52.6 mmol, (obtainable as described in the publication by Ciufoliniet. al. J. Amer. Chem. Soc. 1991, 113, 8016) was dissolved in CH₂Cl₂ (75mL) and treated with diisopropylethylamine (9.2 mL, 52.6 mmol) followedby tri-isopropylsilyl trifluoromethane sulfonate (TIPSTf) (15.3 g, 50.2mmol) at −30° C. The reaction mixture was warmed to 0° C. for 1 h. Themixture was subjected to an aqueous work-up and purified bychromatography on SiO₂ to give4-(2-triisopropylsilanyloxy-ethyl)-cyclohexanone (Intermediate R11, 11.8g (82%). Intermediate R11 was converted via Intermediate R12 to theunsaturated aldehyde,5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde(Intermediate R13)

A solution of TMS-diazomethane (4.61 mL, 9.22 mmol) in THF (60 mL) wasreacted with n-BuLi (5.0 mL, 7.99 mmol) at −78° C. for 0.5 h.5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde(Intermediate R13) was added via cannula. The mixture was reacted at−78° C. for 1 h and at 0° C. for 1 h. After work-up and chromatographicpurification, [2-(3-ethynyl-cyclohex-3-enyl)-ethoxy]-triisopropyl-silane(Intermediate R14) was isolated, 1.44 g (77%). To Intermediate R14 inTHF (70 mL) at 0° C. was injected tetrabutyl ammonium fluoride (TBAF).After 2 h at rt the mixture was subjected to an aqueous work-up. Thematerial was purified by chromatography to give the alcohol,2-(3-ethynyl-cyclohex-3-enyl)-ethanol 0.68 g, (98%). The alcohol wasoxidized by a Swern reaction to the aldehyde stage and aldehyde wassubjected to the applicable step of Method A to yield4-(3-ethynyl-cyclohex-3-enylmethyl)-1H-imidazole (Intermediate R15).

A mixture of NiCl₂ (0.364 g, 2.81 mmol) in EtOH (20 mL) was reacted withNaBH₄ (0.053 mg, 1.40 mmol) at rt for 15 m after saturation of thesolution with hydrogen gas. Ethylene diamine (0.17 g, 2.81 mmol) wasadded followed by the alkynyl imidazol (Intermediate R15, 0.26 g, 1.40mmol) at rt for 45 m under an atmosphere of hydrogen gas. The mixturewas filtered, diluted with chloroform and subjected to an aqueouswork-up. The residue was purified by chromatography on SiO₂ to give4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (72%). To4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (0.09 g, 0.47 mmol) inethanol (3 mL) at 0° C. was added H₂NNH₂.H₂O (0.93 mL, 19.1 mmol)followed by H₂O₂ (30%) (0.488 g, 14.4 mmol) and the mixture was stirredfor 45 m at 0° C. and an additional 6 h at rt. The reaction was quenchedand the material was purified by an aqueous work-up. The imidazolecompound was purified further by isolation of the fumaric acid salt. Thefumarate was converted to the compound4-(3-ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound59) by the applicable step of Method P.

¹H NMR (300 MHz, CD₃OD) δ 6.05 (s, 1H), 5.37 (s, 1H), 2.31 (d, J=6.6 Hz,2H), 2.03–1.10 (m, 9H), 0.97 (t, J=7.5 Hz, 31H).

EXAMPLE S (COMPOUND 60) Procedure for the Preparation of4-(3,4-dimethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 60)

To Intermediate M5 (obtained in accordance with Example M (0.53 g, 1.77mmol) in MeOH (5 ml) was added aqueous KOH (15 ml of a 5M solution) andthe mixture was heated at reflux for 32 h. The mixture was concentratedunder reduced pressure, diluted with H₂O (5 ml) and extractedexhaustively with CHCl₃. The combined organic fractions were washedconsecutively with H₂O and brine, dried (MgSO₄) and concentrated underreduced pressure. The resulting imidazole was recrystallized by stirringin MeOH with an equimolar amount of fumaric acid until all solids haddisappeared followed by the addition of a small amount of diethyl ether.4-(3,4-Dimethyl-cyclohex-3-enylmethyl)-1H-imidazole-fumarate 0.27 g(57%) was recovered as pale yellow crystals.4-(3,4-dimethyl-cyclohex-3-enylmethyl)-1H-imidazole-fumarate wassubjected to the applicable steps of Method P to yield4-(3,4-dimethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 60).

¹H NMR (300 MHz, CD₃OD-d⁴): d 6.04 (s, 1H), 2.29 (d, J=9 Hz, 2H),2.00–1.96 (m, 3H), 1.79–1.69 (m, 3H), 1.59 (s, 6H), 1.21–1.17 (m, 1H).

EXAMPLE T (COMPOUND 61 AND COMPOUND 62) Procedure for the Preparation ofR-(+)-4-(5-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound61) and ofS-(−)-4-(5-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound62)

To 1,3-dithiane (available from Aldrich, 34.1 g, 283.4 mmol) in THF(anhydrous, 373 ml) at −30° C. under argon was added n-BuLi (136.0 ml ofa 2 M solution in cyclohexane) at a rate by which the internaltemperature of the reaction was maintained below −25° C. After additionwas complete the reaction was allowed to warm to −15° C. and stirred for2 hours. The reaction was then allowed to warm to 0° C. and5-fluoro-indan-1-one (Intermediate T1, commercially available fromAldrich) (34.0 g, 226.7 mmol) in THF (anhydrous, 1 L) was added dropwiseover 2 hours. After stirring for 20 hours at 0° C. the reaction wasconcentrated at reduced pressure and the residues were taken up in Et₂O(600 ml) and washed consecutively with 1N HCl, H₂O and brine and thenconcentrated at reduced pressure. This residue was taken up in benzene(1 L) and p-toluenesulfonic acid-H₂O (8.6 g, 45.3 mmol) was added. Thissolution was refluxed in a flask equipped with a Dean Stark trap untilno more H₂O was collected. The reaction was cooled to 20° C. and washedconsecutively with H₂O, saturated aqueous NaHCO₃, brine, dried (MgSO₄),filtered and concentrated at reduced pressure. This residue was taken upin a solution of glacial AcOH (1 L) and concentrated HCl (400 ml) andheated at reflux for 3 hours. The reaction was concentrated at reducedpressure and subjected to azeotropic removal of aqueous liquid bydistillation on a rotary evaporator (3 times) with toluene (100 ml). Theresidues were taken up in Et₂O (200 ml) and washed with H₂O until thewashings were neutral. This solution was extracted 3 times with NaOH (75ml portions of a 5% aqueous solution) and the combined aqueous portionswere washed 3 times with Et₂O (50 ml portions), then treated withdecolorizing charcoal and filtered through celite. The resulting aqueoussolution was cooled to 0° C., carefully acidified to pH 3 with conc. HCland extracted 3 times with CH₂Cl₂. The combined organic portions werewashed with H₂O and brine, dried (MgSO₄), filtered and concentrated atreduced pressure. The resulting solids were recrystallized from hexanesto give 26.2 g (64%) of racemic carboxylic acid (Intermediate T2).

To the racemic carboxylic acid (Intermediate T2, 107.1 g, 595.0 mmol) inrefluxing acetone (500 ml) was added in portions (−)-cinchonidine (175.2g, 595.0 mmol). Additional acetone was gradually added to the refluxingmixture until most solids had gone into solution (final volume was 3.5L). The solution was filtered while hot and then reduced in volume to800 ml and H₂O (900 ml) was added with stirring. The resulting solutionwas allowed to stand for 16 hours at room temperature. The resultingsolid salt was removed by filtration and recrystallized four more timesin similar manner from acetone and H₂O to give a white solid which wastaken up in 0° C. 5N HCl (200 ml). This solution was extracted 3 timeswith Et₂O (200 ml portions) and the combined Et₂O portions were washedsuccessively with 1N HCl, H₂O and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to give 18.9 g (35% of theoretical)of (S)-5-fluoro-indan-1-carboxylic acid (Intermediate T3) as a palesolid with [α]²⁰ _(D)−33.5 (c=3.66, benzene).

(S)-5-Fluoro-indan-1-carboxylic acid (Intermediate T3) was used in thesynthesis ofR-(+)-4-(5-fluoro-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound61) in analogy to the procedure shown in the scheme above for thesynthesis of Compound 62 which is described below. Compound 61: [α]²⁰_(D)+12.5 (c=0.6, DMSO).

¹H NMR (500 MHz, DMSO-d⁶) δ 9.80 (s, 1H), 9.42 (s, 1H), 7.11–7.08 (m,1H), 7.01–6.99 (m, 1H), 6.91–6.87 (m, 1H), 5.93 (s, 1H), 3.30–3.25 (m,1H), 2.88–2.70 (m, 2H), 2.65–2.58 (m, 1H), 2.32–2.10 (m, 2H), 1.71–1.66(m, 1H).

The combined mother liquors from the resolution of Intermediate T3 wereconcentrated under reduced pressure until no acetone remained andacidified to pH 3 with 0° C. 5N HCl. This solution was extracted 3 timeswith Et₂O (200 ml portions) and the combined Et₂O portions were washedsuccessively with 1N HCl, H₂O and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to give a yellow solid (71 g). Thisresidue was recrystallized from hexane to give pure5-fluoro-indan-1-carboxylic acid (Intermediate 2a, 58.6 g, 325.5 mmol)which was enriched in the R enantiomer. To Intermediate 2a in refluxingacetone (1 L) was added pulverized brucine (128.4 g, 325.5 mmol). Aftermost solids had dissolved the solution was hot filtered and reheated toreflux as H₂O (1 L) was added gradually. Excess acetone was boiled offuntil the solution became hazy. The solution was allowed to stand in arecrystallization dish for 1 month before solids appeared. The resultantsolids were broken up, filtered off and recrystallized four more timesin similar manner from acetone and H₂O to give a buff colored solidwhich was taken up in 0° C. 1N HCl (150 ml). This solution was extracted3 times with Et₂O (75 ml portions) and the combined Et₂O portions werewashed successively with 1N HCl, H₂O and brine, dried (MgSO₄), filteredand concentrated under reduced pressure to give 6.13 g of(R)-5-fluoro-indan-1-carboxylic acid (Intermediate T4) as a pale solidwhich rotates sodium light at 20° C. with [α]²⁰ _(D)+31.8 (c=4.49,benzene).

To a solution of LAH (33.8 ml of a 1M solution in THF) in THF(anhydrous, 30 ml) at 0° C. under argon was added the carboxylic acid(Intermediate T4, 3.04 g, 16.90 mmol) in THF (anhydrous, 30 ml) dropwisevia syringe. This mixture was stirred 30 minutes at 0° C. and thenallowed to stir at 20° C. for 1 hour. The reaction was then recooled to0° C. and quenched with the successive addition of H₂O (1.3 ml), 15%aqueous NaOH (1.3 ml) and H₂O (2.6 ml). This mixture was stirred 30minutes at 20° C. and then filtered. The filtrate was concentrated underreduced pressure and the residues were purified by chromatography onSiO₂ with 20% EtOAc:hexanes to give 2.69 g of the alcohol (IntermediateT5, 96%) with [α]²⁰ _(D)+17.1 (c=6.04, benzene).

Triphenylphosphine (10.62 g, 40.48 mmol) in a solution of THF(anhydrous, 125 ml) at 0° C. under argon was treated with DEAD (6.77 g,38.86 mmol). After stirring 5 minutes the alcohol (Intermediate T5, 2.69g, 16.93 mmol) and acetone cyanohydrin (3.31 g, 38.86 mmol) in THF(anhydrous, 50 ml) were added concurrently via cannula. This mixture wasallowed to stir at 20° C. for 20 hours. The mixture was concentratedunder reduced pressure, the residues were taken up in Et₂O, washedconsecutively with saturated aqueous K₂CO₃, H₂O and brine, dried (MgSO₄)and concentrated under reduced pressure. The residues were purified bychromatography on SiO₂ with 20% EtOAc:hexanes to give 2.69 g of thenitrile (Intermediate T6). This mixture was carried on without furtherpurification.

To the nitrile (Intermediate T6, 2.00 g, 11.43 mmol) in Et₂O (anhydrous,50 ml) at −78° C. under argon was added DIBAL (22.9 ml of a 1 M solutionin THF) and the reaction was allowed to warm gradually to 40° C.Additional DIBAL (21.0 ml of a 1 M solution in THF) was added to thereaction mixture at −40° C. over a period of 24 hours until no startingmaterial was visible by thin layer chromatography. The reaction wasquenched with a saturated aqueous solution of sodium potassium tartrate.After stirring a 20° C. for 1 hour the solids were filtered off and thefiltrate was taken up in Et₂O and washed consecutively with H₂O andbrine, dried (MgSO₄) and concentrated under reduced pressure. Theresidues were purified by chromatography on SiO₂ with 10% EtOAc:hexanesto give 0.94 g of pure aldehyde (Intermediate T7, 47%) with [α]²⁰_(D)−2.5 (c=5.58, benzene).

A solution of the aldehyde (Intermediate T7, 0.90 g, 5.06 mmol) in EtOH(anhydrous, 15 ml) was treated with tosylmethyl isocyanide (TosMIC)(0.94 g, 4.81 mmol) and NaCN (0.013 g, 0.25 mmol) at 20° C. for 20minutes. This mixture was concentrated under reduced pressure and theresulting residue was taken up in MeOH saturated with NH3 (anhydrous, 10ml) and heated in a sealed tube at 100° C. for 16 hours. The reactionmixture was concentrated under reduced pressure and purified bychromatography on SiO₂ with 10% MeOH:CH₂Cl₂ to give 0.59 g (54%) of theimidazole (Intermediate T8) which rotates sodium light at 20° C. with[α]²⁰ _(D)−14.7 (c=3.72, MeOH).

To the imidazole (Intermediate T8, 0.55 g, 2.56 mmol) in a solution ofTHF (15 ml) and H₂O (15 ml) was added NaHCO₃ (2.15 g, 25.60 mmol)followed by phenyl chloroformate (1.00 g, 6.40 mmol). After heating at65° C. for 2 hours the mixture was cooled and washed consecutively withH₂O and brine, dried (MgSO₄) and concentrated under reduced pressure.The residues were taken up in EtOH (10 ml) and H₂O (15 ml), treated withNa₂CO₃ (0.77 ml, 7.29 mmol) and heated at reflux for 1 hour. Aftercooling the solids were filtered off, washed with H₂O, Et₂O and driedfor 20 hours under high vacuum to give (Compound 62, 0.39 g (66%) with[α]²⁰ _(D)−10.0 (c=1.08, in DMSO). ¹H NMR (300 MHz, DMSO-d⁶) δ 9.80 (s,1H), 9.42 (s, 1H), 7.15–7.06 (m, 1H), 7.04–6.97 (m, 1H), 6.96–6.87 (m,1H), 5.93 (s, 1H), 3.35–3.21 (m, 1H), 2.92–2.68 (m, 2H), 2.67–2.56 (m,1H), 2.32–2.09 (m, 2H), 1.76–1.62 (m, 1H).

EXAMPLE U (COMPOUND 63) Procedure for the Preparation of4-(5-hydroxy-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 63)

A solution of 5-hydroxyindanone (available from Aldrich, 1.48 g, 10mmol) in CH₂Cl₂ (10 mL) and dihydropyran (5 mL) was treated with camphorsulphonic acid (˜50 mg catalytic amount) at 0° C. The mixture wasallowed to warm to room temperature and stirring was continued for 2 h.The mixture was subjected to an aqueous work-up, extracted with ether,dried over MgSO₄, filtered and evaporated to dryness. The protectedindanone, 5-(tetrahydro-pyran-2-yloxy)-indan-1-one was used in the nextstep without further purification.

Use of 5-(tetrahydro-pyran-2-yloxy)-indan-1-one in the applicable stepsof Method A and Method P produced Compound 63. Note: a separation of theTHP protected compound,4-[5-(tetrahydro-pyran-2-yloxy)-indan-1-ylmethyl]-1H-imidazole from thehydroxy compound 1-(1H-imidazol-4-ylmethyl)-indan-5-ol (Intermediate U4,shown in the scheme above) was accomplished by chromatography on SiO₂with 3 to 5% NH₃—MeOH in CH₂Cl₂.4-(5-hydroxy-indan-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 63):

¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.93 (d, J=13 Hz, 1H), 6.62–6.53 (m, 2H),6.01 (s, 1H), 2.83–2.68 (m, 4H), 2.43–2.35 (m, 1H), 2.24–2.17 (m, 1H),1.16–1.69 (m, 1H).

EXAMPLE V (COMPOUND 64) Procedure for Preparation4-(2-ethyl-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 64)

2-Bromo-3-methyl-cyclopent-2-enone (Intermediate V1, commerciallyavailable from Aldrich) (18 mmol) was dissolved in 0.4M CeCl₃ 7H₂O inMeOH (66 mL) at 0° C. Sodium borohydride (20 mmol) was addedportion-wise and stirring was continued for 10 m after addition wascomplete. The mixture was quenched with saturated NH₄Cl and extractedwith ether. The combined organic layers were washed with sat. NH₄C₁,H₂O, brine, and dried over Na₂SO₄, filtered and evaporated to dryness.The material was purified by column chromatography 15% EtOAc:Hx to give2-bromo-3-methyl-cyclopent-2-enol (Intermediate V2, ˜80%).

The alcohol (Intermediate V2, 16 mmol) in THF (30 mL) at 0° C. wastreated with ethyl magnesium bromide (40 mmol). The catalyst,1,3-bis(diphenylphosphino)propane nickel (11) chloride (0.75 mmol)(NiCl₂dppp) was added in one portion and the mixture was heated toreflux for 3 hours following the procedure of Organ et al. J. Org. Chem.1997, 62, 1523, incorporated herein by reference.) The reaction mixturewas cooled to rt and quenched with sat. NH₄Cl solution. The mixture wasfiltered and partitioned between brine and diethyl ether. The organiclayer was removed and dried over Na₂SO₄, filtered and concentrated undervacuum. The oil was purified by chromatography on SiO₂ with 20% EtOAc:Hxto yield 2-ethyl-3-methyl-cyclopent-2-enol (Intermediate V3). Use of thealcohol (Intermediate V3) in the applicable steps of Method A and MethodP produced4-(2-ethyl-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one(Compound 64). ¹H NMR (300 MHz, CD₃OD-d⁴): δ 6.03 (s, 1H), 2.88 (brs,1H), 2.65–2.59 (m, 1H), 2.27–1.83 (series of m, 6H), 1.62 (s, 3H),1.54–1.45 (m, 1H), 0.97 (t, J=6 Hz, 3H).

1. A compound of the formula

where X is O or S; the dashed lines represent a bond, or absence of bondwith the proviso that only one double bond is present in the ring andthat two adjoining dashed lines do not both represent a bond; R₁, R₂,R₃, and R₄ are independently H, phenyl, said phenyl group beingoptionally substituted independently with one, two or three C₁₋₆alkyl,SO₃H, N₃, halogen, CN, NO₂, NH₂, C₁₋₆alkoxy, C₁₋₆thioalkoxy,C₁₋₆alkylamino, C₁₋₆dialkylamino, C₂₋₆alkynyl or C₂₋₆alkenyl groups, orsaid R₁, R₂, R₃, and R₄ groups are independently alkyl of 1 to 4carbons, cycloalkyl of 3 to 5 carbons, CH₂CN, CH₂SR₅, CH₂NR₆R₆, COR₅,CH₂OR₅, OR₆, SR₆. NR₆R₆, alkenyl having 1 to 4 carbons, alkynyl having 1to 4 carbons, cycloalkyl having 3 to 6 carbons, F, Cl, Br, I, CF₃, orCN, an oxygen double bonded to the ring carbon with the proviso that theadjacent dashed line within the ring represents absence of a bond; R₅ isH, OR₇, alkyl of 1 to 4 carbons, CF₃, cycloalkyl of 3 to 6 carbons,phenyl, phenyl substituted with one or two alkyl groups of 1 to 4carbons, with F, Cl, Br, I, or with CF₃; R₆ is H, alkyl of 1 to 4carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl, phenyl substitutedwith one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I, orwith CF₃, and R₇ is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3to 6 carbons, phenyl, phenyl substituted with one or two alkyl groups of1 to 4 carbons, with F, Cl, Br, I, or with CF₃.
 2. A compound inaccordance with claim 1 where X is S.
 3. A compound in accordance withclaim 2 that has the formula